Nlrp3 modulators

ABSTRACT

The present invention provides compounds of Formula (I): 
     
       
         
         
             
             
         
       
     
     wherein all of the variables are as defined herein. These compounds are modulators of NLRP3, which may be used as medicaments for the treatment of proliferative disorders, such as cancer in a subject (e.g., a human).

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of patent application Ser.No. 16/629,980, filed Jan. 10, 2020, (now allowed), which is a 371 ofInternational Application No. PCT/US2018/041723 filed on Jul. 12, 2018,which claims the priority benefit of U.S. Provisional Application No.62/532,932, filed Jul. 14, 2017, U.S. Provisional Application No.62/662,405, filed Apr. 25, 2018, and U.S. Provisional Application No.62/689,412, filed Jun. 25, 2018; the contents of which are hereinincorporated by reference in their entirety.

TECHNICAL FIELD

This disclosure features chemical entities (e.g., a compound or apharmaceutically acceptable salt, and/or hydrate, and/or cocrystal,and/or drug combination of the compound) that modulate (e.g., agonizesor partially agonizes) NLRP3 that are useful, e.g., for treating acondition, disease or disorder in which an increase in NLRP3 signalingmay correct a deficiency in innate immune activity that contributes tothe pathology and/or symptoms and/or progression and/or treatmentrefractory state of the condition, disease or disorder (e.g., cancerswith low T-cell infiltration) in a subject (e.g., a human). Thisdisclosure also features compositions as well as other methods of usingand making the same.

BACKGROUND

Nucleotide-binding oligomerization domain-like receptors (“NLRs”)include a family of intracellular receptors that detectpathogen-associated molecular patterns (“PAMPs”) and endogenousmolecules (see, e.g., Ting, J. P. Y. et al., “The NLR gene family: astandard nomenclature,” Immunity, 28(3):285-287, (2008)).

NLRPs represent a subfamily of NLRs that include a Pyrin domain and areconstituted by proteins such as NLRP1, NLRP3, NLRP4, NLRP6, NLRP7, andNLRP12. NLRPs are believed to be involved with the formation ofmultiprotein complexes termed inflammasomes (see, e.g., Chaput, C. etal., “NOD-like receptors in lung diseases,” Frontiers in Immunology, 4:article 393, (2013)). These complexes typically include one or two NLRproteins, the adapter molecule apoptosis associated speck-likecontaining a CARD domain (ASC) and pro-caspase-1 F (see, e.g.,Bauernfeind, F and Hornung, V. “Of inflammasomes and pathogens—sensingof microbes by the inflammasome,” EMBO Molecular Medicine, 5(6):814-826,(2013)).

One such inflammasome is formed by the NLRP3 scaffold, the ASC adaptorand pro-caspase-1 (see, e.g., Hirota, J. A., et al., “The airwayepithelium nucleotide-binding domain and leucine-rich repeat protein 3inflammasome is activated by urban particulate matter,” Journal ofAllergy and Clinical Immunology, 129(4):1116.e6-1125.e6, (2012)), andits expression is believed to be induced by inflammatory cytokines andTLR agonists in myeloid cells and human bronchial epithelial cells(Id.). The NLRP3 inflammasome is believed to mediate thecaspase-1-dependent conversion of pro-IL-1β and pro-IL-18 to IL-1β andIL-18. Further, IL-1β and IL-18 have potential in the treatment ofvarious types of cancer (see, e.g., Chen, L-C. et al., EMBO Mol Med.,4(12):1276-1293 (2012) and Tse, B. W-C. et al., PLoS One, 6(9):e24241(2011)). IL-18 has been shown to override resistance to checkpointinhibitors in colon cancer animal tumor models (see e.g., Ma, Z. et al.,Clin. Cancer Res. January 11. (2016) DOI:10.1158/1078-0432.CCR-15-1655).

SUMMARY

This disclosure features chemical entities (e.g., a compound or apharmaceutically acceptable salt, and/or hydrate, and/or cocrystal,and/or drug combination of the compound) that modulate (e.g., agonizesor partially agonizes) NLRP3 that are useful, e.g., for treating acondition, disease or disorder in which an increase in NLRP3 signalingmay correct a deficiency in innate immune activity contributes to thepathology and/or symptoms and/or progression and/or treatment refractorystate of the condition, disease or disorder (e.g., cancers with lowT-cell infiltration) in a subject (e.g., a human). This disclosure alsofeatures compositions as well as other methods of using and making thesame.

An “agonist” of NLRP3 includes compounds that, at the protein level,directly bind or modify NLRP3 such that an activity of NLRP3 isincreased, e.g., by activation, stabilization, altered distribution, orotherwise.

Certain compounds described herein that agonize NLRP3 to a lesser extentthan a NLRP3 full agonist can function in assays as antagonists as wellas agonists. These compounds antagonize activation of NLRP3 by a NLRP3full agonist because they prevent the full effect of NLRP3 interaction.However, the compounds also, on their own, activate some NLRP3 activity,typically less than a corresponding amount of the NLRP3 full agonist.Such compounds may be referred to as “partial agonists of NLRP3”.

In some embodiments, the compounds described herein are agonists (e.g.full agonists) of NLRP3. In other embodiments, the compounds describedherein are partial agonists of NLRP3.

Generally, a receptor exists in an active (Ra) and an inactive (Ri)conformation. Certain compounds that affect the receptor can alter theratio of Ra to Ri (Ra/Ri). For example, a full agonist increases theratio of Ra/Ri and can cause a “maximal”, saturating effect. A partialagonist, when bound to the receptor, gives a response that is lower thanthat elicited by a full agonist (e.g., an endogenous agonist). Thus, theRa/Ri for a partial agonist is less than for a full agonist. However,the potency of a partial agonist may be greater or less than that of thefull agonist.

In one aspect, compounds of Formula (I), or a pharmaceuticallyacceptable salt thereof, are featured:

in which W, W′, R³, and R⁴ can be as defined anywhere herein.

In one aspect, methods for modulating (e.g., agonizing, partiallyagonizing, antagonizing) NLRP3 activity are featured that includecontacting NLRP3 with a chemical entity described herein (e.g., acompound described generically or specifically herein or apharmaceutically acceptable salt thereof or compositions containing thesame). In preferred embodiments, methods for modulating NLRP3 activityare agonizing and partially agonizing. In certain embodiments, methodsfor modulating NLRP3 activity are agonizing. In certain embodiments,methods for modulating NLRP3 activity are partially agonizing. Methodsinclude in vitro methods, e.g., contacting a sample that includes one ormore cells comprising NLRP3 (e.g., THP-1 cells) with the chemicalentity. Methods can also include in vivo methods; e.g., administeringthe chemical entity to a subject (e.g., a human) having a disease inwhich an increase in NLRP3 signaling may correct a deficiency in innateimmune activity that contributes to the pathology and/or symptoms and/orprogression of the disease (e.g., cancer; e.g., a refractory cancer).

In some embodiments, compounds of the invention are useful for treatinga condition, disease or disorder in which a decrease in NLRP3 activity(e.g., a condition, disease or disorder associated with repressed orimpaired NLRP3 signaling) contributes to the pathology and/or symptomsand/or progression of the condition, disease or disorder (e.g., cancer)in a subject (e.g., a human).

A cancer is said to be refractory when it does not respond to (or isresistant to) cancer treatment. Refractory cancer is also known asresistant cancer.

In another aspect, methods of treating cancer are featured that includeadministering to a subject in need of such treatment an effective amountof a chemical entity described herein (e.g., a compound describedgenerically or specifically herein or a pharmaceutically acceptable saltthereof or compositions containing the same). In some embodiments, thecancer may be a refractory cancer.

In a further aspect, methods of treatment of a disease in which anincrease in NLRP3 signaling may correct a deficiency in innate immuneactivity that contributes to the pathology and/or symptoms and/orprogression of the disease are featured that include administering to asubject in need of such treatment an effective amount of a chemicalentity described herein (e.g., a compound described generically orspecifically herein or a pharmaceutically acceptable salt thereof orcompositions containing the same).

In another aspect, methods of treatment are featured that includeadministering to a subject having a disease in which an increase inNLRP3 signaling may correct a deficiency in innate immune activity thatcontributes to the pathology and/or symptoms and/or progression of thedisease an effective amount of a chemical entity described herein (e.g.,a compound described generically or specifically herein or apharmaceutically acceptable salt thereof or compositions containing thesame).

In a further aspect, methods of treatment are featured that includeadministering to a subject a chemical entity described herein (e.g., acompound described generically or specifically herein or apharmaceutically acceptable salt thereof or compositions containing thesame), wherein the chemical entity is administered in an amounteffective to treat a disease in which an increase in NLRP3 signaling maycorrect a deficiency in innate immune activity that contributes to thepathology and/or symptoms and/or progression of the disease, therebytreating the disease.

Embodiments can include one or more of the following features.

The chemical entity can be administered in combination with one or moreadditional cancer therapies (e.g., surgery, radiotherapy, chemotherapy,toxin therapy, immunotherapy, cryotherapy or gene therapy, or acombination thereof; e.g., cancer therapies that include administeringone or more (e.g., two, three, four, five, six, or more) additionalanti-cancer agents. Non-limiting examples of additional anti-canceragents (chemotherapeutic agents) are selected from an alkylating agent(e.g., cisplatin, carboplatin, mechlorethamine, cyclophosphamide,chlorambucil, ifosfamide and/or oxaliplatin); an anti-metabolite (e.g.,azathioprine and/or mercaptopurine); a terpenoid (e.g., a vinca alkaloidand/or a taxane; e.g., Vincristine, Vinblastine, Vinorelbine and/orVindesine, Taxol, Paclitaxel and/or Docetaxel); a topoisomerase (e.g., atype I topoisomerase and/or a type 2 topoisomerase; e.g., camptothecins,such as irinotecan and/or topotecan; amsacrine, etoposide, etoposidephosphate and/or teniposide); a cytotoxic antibiotic (e.g., actinomycin,anthracyclines, doxorubicin, daunorubicin, valrubicin, idarubicin,epirubicin, bleomycin, plicamycin and/or mitomycin); a hormone (e.g., alutenizing hormone releasing hormone agonist; e.g., leuprolidine,goserelin, triptorelin, histrelin, bicalutamide, flutamide and/ornilutamide); an antibody (e.g., Abciximab, Adalimumab, Alemtuzumab,Atlizumab, Basiliximab, Belimumab, Bevacizumab, Bretuximab vedotin,Canakinumab, Cetuximab, Ceertolizumab pegol, Daclizumab, Denosumab,Eculizumab, Efalizumab, Gemtuzumab, Golimumab, Ibritumomab tiuxetan,Infliximab, Ipilimumab, Muromonab-CD3, Natalizumab, Ofatumumab,Omalizumab, Palivizumab, Panitumuab, Ranibizumab, Rituximab,Tocilizumab, Tositumomab and/or Trastuzumab); an anti-angiogenic agent;a cytokine; a thrombotic agent; a growth inhibitory agent; ananti-helminthic agent; and an immune checkpoint inhibitor that targetsan immune checkpoint receptor selected from CTLA-4, PD-1, PD-L1,PD-1-PD-L1, PD-1-PD-L2, T cell immunoglobulin and mucin 3 (TIM3 orHAVCR2), Galectin 9-TIM3, Phosphatidylserine-TIM3, lymphocyte activationgene 3 protein (LAG3), MHC class II-LAG3, 4-1BB-4-1BB ligand, OX40-OX40ligand, GITR, GITR ligand-GITR, CD27, CD70-CD27, TNFRSF25,TNFRSF25-TL1A, CD40L, CD40-CD40 ligand, HVEM-LIGHT-LTA, HVEM, HVEM-BTLA,HVEM-CD160, HVEM-LIGHT, HVEM-BTLA-CD160, CD80, CD80-PDL-1, PDL2-CD80,CD244, CD48-CD244, CD244, ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, VISTA,TMIGD2, HHLA2-TMIGD2, Butyrophilins, including BTNL2, Siglec family,TIGIT and PVR family members, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICAand MICB, CD244, CD28, CD86-CD28, CD86-CTLA, CD80-CD28,Phosphatidylserine, TIM3, Phosphatidylserine-TIM3, SIRPA-CD47, VEGF,Neuropilin, CD160, CD30, and CD155 (e.g., CTLA-4 or PD1 or PD-L 1) andother immunomodulatory agents, such as interleukin-2 (IL-2), indoleamine2,3-dioxygenase (IDO), IL-10, transforming growth factor-β (TGFβ), CD39,CD73 Adenosine-CD39-CD73, and CXCR4-CXCL12.

The subject can have cancer; e.g., the subject has undergone and/or isundergoing and/or will undergo one or more cancer therapies.

Non-limiting examples of cancer include acute myeloid leukemia,adrenocortical carcinoma, Kaposi sarcoma, lymphoma, anal cancer,appendix cancer, teratoid/rhabdoid tumor, basal cell carcinoma, bileduct cancer, bladder cancer, bone cancer, brain cancer, breast cancer,bronchial tumor, carcinoid tumor, cardiac tumor, cervical cancer,chordoma, chronic lymphocytic leukemia, chronic myeloproliferativeneoplasm, colon cancer, colorectal cancer, craniopharyngioma, bile ductcancer, endometrial cancer, ependymoma, esophageal cancer,esthesioneuroblastoma, Ewing sarcoma, eye cancer, fallopian tube cancer,gallbladder cancer, gastrointestinal carcinoid tumor, gastrointestinalstromal tumor, germ cell tumor, hairy cell leukemia, head and neckcancer, heart cancer, liver cancer, hypopharngeal cancer, pancreaticcancer, kidney cancer, laryngeal cancer, chronic myelogenous leukemia,lip and oral cavity cancer, lung cancer, melanoma, Merkel cellcarcinoma, mesothelioma, mouth cancer, oral cancer, osteosarcoma,ovarian cancer, penile cancer, pharyngeal cancer, prostate cancer,rectal cancer, salivary gland cancer, skin cancer, small intestinecancer, soft tissue sarcoma, testicular cancer, throat cancer, thyroidcancer, urethral cancer, uterine cancer, vaginal cancer, and vulvarcancer.

In other embodiments, the mammal has been identified as having a canceror an infectious disease. Representative infectious diseases include,without limitation, Acinobacter infection, actinomycosis, Africansleeping sickness, acquired immunodeficiency syndrome, amebiasis,anaplasmosis, anthrax, Arcanobacterium haemolyticum infection, Argentinehemorrhagic fever, ascariasis, aspergillosis, astrovirus infection,babesiosis, Bacillus cereus infection, bacterial pneumonia, bacterialvaginosis, Bacteroides infection, balantidiasis, Baylisascarisinfection, BK virus infection, black piedra, Blastocystic hominisinfection, blastomycosis, Bolivian hemorrhagic fever, botulism,Brazilian hemorrhagic fever, brucellosis, bubonic plaque, Burkholderiinfection, Buruli ulcer, Calicivirus infection, camptobacteriosis,candidiasis, cat-scratch disease, cellulitis, Chagas disease, chancroid,chickenpox, chikungunya, chlamydia, Chlamydophila pneumoniae infection,cholera, chromoblastomycosis, clonorchiasis, Clostridium difficileinfection, coccidioidomycosis, Colorado tick fever, common cold,Creutzfeldt-Jakob disease, Crimean-Congo hemorrhagic fever,crytococcosis, cryptosporidiosis, cutaneous larva migrans,cyclosporiasis, cysticercosis, cytomegalovirus infection, dengue fever,Desmodesmus infection, deintamoebiasis, diphtheria, diphyllobothriasis,dracunculiasis, ebola hemorrhagic fever, echinococcosis, ehrlichiosis,enterobiasis, Enterococcus infection, Enterovirus infection, epidemictyphus, erythema infection, exanthema subitum, fasciolopsiasis,fasciolosis, fatal familial insomnia, filariasis, food poisoning byClostridium myonecrosis, free-living amebic infection, Fusobacteriuminfection, gas gangrene, geotrichosis, Gerstmann-Straussler-Scheinkersyndrome, giardiasis, glanders, gnathostomiasis, gonorrhea, granulomainguinale, Group A streptococcal infection, Group B streptococcalinfection, Haemophilus influenzae infection, hand foot and mouthdisease, hantavirus pulmonary syndrome, Heartland virus disease,Heliobacter pylori infection, hemolytic-uremic syndrome, hemorrhagicfever with renal syndrome, hepatitis A, hepatitis B, hepatitis C,hepatitis D, hepatitis E, herpes simplex, histoplasmosis, hookworminfection, human bocavirus infection, human ewingii ehrlichiosis, humangranulocyte anaplasmosis, human metapneuomovirus infection, humanmonocytic ehrlichiosis, human papillomavirus infection, humanparainfluenza virus infection, hymenolepiasis, Epstein-Barr virusinfectious mononucleosis, influenza, isosporiasis, Kawasaki disease,keratitis, Kingella kingae infection, kuru, lassa fever, Legionnaires'disease, Pontiac fever, leishmaniasis, leprosy, leptospirosis,listeriosis, lyme disease, lymphatic filariasis, lymphocyticchoriomeningitis, malaria, Marburg hemorrhagic fever, measles, MiddleEast respiratory syndrome, melioidosis, meningitis, meningococcaldisease, metagonimiasis, microsporidiosis, molluscum contagiosum,monkeypox, mumps, murine typhus, mycoplasma pneumonia, mycetoma,myiasis, neonatal conjunctivitis, variant Creutzfeldt-Jakob disease,nocardiosis, onchocerciasis, paracoccidioidomycosis, paragonimiasis,pasteurellosis, pediculosis capitis, pediculosis corporis, pediculosispubis, pelvic inflammatory disease, pertussis, plague, pneumonia,poliomyelitis, Prevotella infection, primary amoebicmeningoencephalitis, progressive multifocal leukoencephalopathy,psittacosis, Q fever, rabies, relapsing fever, respiratory syncytialvirus infection, rhinosporidiosis, rhinovirus infection, rickettsialinfection, rickettsialpox, Rift Valley Fever, Rocky Mountain spottedfever, rotavirus infection, rubella, salmonellosis, severe acuterespiratory syndrome, scabies, schistosomiasis, sepsis, shigellosis,shingles, smallpox, sporothrichosis, staphylococcal food poisoning,staphylococcal infection, strongyloidiasis, subacute sclerosingpanencephalitis, syphilis, taeniasis, tetanus, tinea barabe, tineacapitis, tinea corporis, tinea cruris, tinea manum, tinea nigra, tineapedis, tinea unguium, tinea versicolor, toxocariasis, trachoma,toxoplasmosis, trichinosis, trichomoniasis, trichuriasis, tuberculosis,tularemia, typhoid fever, Ureaplasma urealyticum infection, valleyfever, Venezuelan hemorrhagic fever, viral pneumonia, West Nile fever,white piedra, Yersinia psuedotuberculosis infection, yersiniosis, yellowfever, and zygomycosis.

The chemical entity can be administered intratumorally.

The chemical entity can be administered systemically (including but notlimited to orally, subcutaneously, intramuscular, intravenously).

The methods can further include identifying the subject.

Other embodiments include those described in the Detailed Descriptionand/or in the claims.

Additional Definitions

To facilitate understanding of the disclosure set forth herein, a numberof additional terms are defined below. Generally, the nomenclature usedherein and the laboratory procedures in organic chemistry, medicinalchemistry, and pharmacology described herein are those well-known andcommonly employed in the art. Unless defined otherwise, all technicaland scientific terms used herein generally have the same meaning ascommonly understood by one of ordinary skill in the art to which thisdisclosure belongs.

Unless specifically stated otherwise herein, references made in thesingular may also include the plural. For example, “a” and “an” mayrefer to either one, or one or more.

Unless otherwise indicated, any heteroatom with unsatisfied valences isassumed to have hydrogen atoms sufficient to satisfy the valences.

Throughout the specification and the appended claims, a given chemicalformula or name shall encompass all stereo and optical isomers andracemates thereof where such isomers exist. Unless otherwise indicated,all chiral (enantiomeric and diastereomeric) and racemic forms arewithin the scope of the invention. Many geometric isomers of C═C doublebonds, C═N double bonds, ring systems, and the like can also be presentin the compounds, and all such stable isomers are contemplated in thepresent invention. Cis- and trans- (or E- and Z-) geometric isomers ofthe compounds of the present invention are described and may be isolatedas a mixture of isomers or as separated isomeric forms. The presentcompounds can be isolated in optically active or racemic forms.Optically active forms may be prepared by resolution of racemic forms orby synthesis from optically active starting materials. All processesused to prepare compounds of the present invention and intermediatesmade therein are considered to be part of the present invention. Whenenantiomeric or diastereomeric products are prepared, they may beseparated by conventional methods, for example, by chromatography orfractional crystallization. Depending on the process conditions the endproducts of the present invention are obtained either in free (neutral)or salt form. Both the free form and the salts of these end products arewithin the scope of the invention. If so desired, one form of a compoundmay be converted into another form. A free base or acid may be convertedinto a salt; a salt may be converted into the free compound or anothersalt; a mixture of isomeric compounds of the present invention may beseparated into the individual isomers. Compounds of the presentinvention, free form and salts thereof, may exist in multiple tautomericforms, in which hydrogen atoms are transposed to other parts of themolecules and the chemical bonds between the atoms of the molecules areconsequently rearranged. It should be understood that all tautomericforms, insofar as they may exist, are included within the invention.

As used herein, the term “NLRP3” is meant to include, withoutlimitation, nucleic acids, polynucleotides, oligonucleotides, sense andantisense polynucleotide strands, complementary sequences, peptides,polypeptides, proteins, homologous and/or orthologous NLRP3 molecules,isoforms, precursors, mutants, variants, derivatives, splice variants,alleles, different species, and active fragments thereof.

The term “acceptable” with respect to a formulation, composition oringredient, as used herein, means having no persistent detrimentaleffect on the general health of the subject being treated.

“API” refers to an active pharmaceutical ingredient.

The terms “effective amount” or “therapeutically effective amount,” asused herein, refer to a sufficient amount of a chemical entity (e.g., acompound exhibiting activity as a mitochondrial uncoupling agent or apharmaceutically acceptable salt and/or hydrate and/or cocrystalthereof; e.g., a compound, such as niclosamide or a pharmaceuticallyacceptable salt and/or hydrate and/or cocrystal thereof; e.g., acompound, such as a niclosamide analog, or a pharmaceutically acceptablesalt and/or hydrate and/or cocrystal thereof) being administered whichwill relieve to some extent one or more of the symptoms of the diseaseor condition being treated. The result includes reduction and/oralleviation of the signs, symptoms, or causes of a disease, or any otherdesired alteration of a biological system. For example, an “effectiveamount” for therapeutic uses is the amount of the composition comprisinga compound as disclosed herein required to provide a clinicallysignificant decrease in disease symptoms. An appropriate “effective”amount in any individual case is determined using any suitabletechnique, such as a dose escalation study.

The term “excipient” or “pharmaceutically acceptable excipient” means apharmaceutically-acceptable material, composition, or vehicle, such as aliquid or solid filler, diluent, carrier, solvent, or encapsulatingmaterial. In one embodiment, each component is “pharmaceuticallyacceptable” in the sense of being compatible with the other ingredientsof a pharmaceutical formulation, and suitable for use in contact withthe tissue or organ of humans and animals without excessive toxicity,irritation, allergic response, immunogenicity, or other problems orcomplications, commensurate with a reasonable benefit/risk ratio. See.e.g., Remington: The Science and Practice of Pharmacy. 22nd Edition,Pharmaceutical Press, London, UK (2012); Handbook of PharmaceuticalExcipients. 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and theAmerican Pharmaceutical Association: (2009); Handbook of PharmaceuticalAdditives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: (2007);Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRCPress LLC: Boca Raton, Fla., (2009).

The term “pharmaceutically acceptable salt” refers to a formulation of acompound that does not cause significant irritation to an organism towhich it is administered and does not abrogate the biological activityand properties of the compound. In certain instances, pharmaceuticallyacceptable salts are obtained by reacting a compound described herein,with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid,nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, salicylic acid and the like. In some instances,pharmaceutically acceptable salts are obtained by reacting a compoundhaving acidic group described herein with a base to form a salt such asan ammonium salt, an alkali metal salt, such as a sodium or a potassiumsalt, an alkaline earth metal salt, such as a calcium or a magnesiumsalt, a salt of organic bases such as dicyclohexylamine,N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts withamino acids such as arginine, lysine, and the like, or by other methodspreviously determined. The pharmacologically acceptable salt is notspecifically limited as far as it can be used in medicaments. Examplesof a salt that the compounds described hereinform with a base includethe following: salts thereof with inorganic bases such as sodium,potassium, magnesium, calcium, and aluminum; salts thereof with organicbases such as methylamine, ethylamine and ethanolamine; salts thereofwith basic amino acids such as lysine and omithine; and ammonium salt.The salts may be acid addition salts, which are specifically exemplifiedby acid addition salts with the following: mineral acids such ashydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid,nitric acid, and phosphoric acid:organic acids such as formic acid,acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid,fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid,citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic aminoacids such as aspartic acid and glutamic acid.

The term “pharmaceutical composition” refers to a mixture of a compounddescribed herein with other chemical components (referred tocollectively herein as “excipients”), such as carriers, stabilizers,diluents, dispersing agents, suspending agents, and/or thickeningagents. The pharmaceutical composition facilitates administration of thecompound to an organism. Multiple techniques of administering a compoundexist in the art including, but not limited to: rectal, oral,intravenous, aerosol, parenteral, ophthalmic, pulmonary, and topicaladministration.

The term “subject” refers to an animal, including, but not limited to, aprimate (e.g., human), monkey, cow, pig, sheep, goat, horse, dog, cat,rabbit, rat, or mouse. The terms “subject” and “patient” are usedinterchangeably herein in reference, for example, to a mammaliansubject, such as a human.

The terms “treat,” “treating,” and “treatment,” in the context oftreating a disease or disorder, are meant to include alleviating orabrogating a disorder, disease, or condition, or one or more of thesymptoms associated with the disorder, disease, or condition; or toslowing the progression, spread or worsening of a disease, disorder orcondition or of one or more symptoms thereof. The “treatment of cancer”,refers to one or more of the following effects: (1) inhibition, to someextent, of tumor growth, including, (i) slowing down and (ii) completegrowth arrest; (2) reduction in the number of tumor cells; (3)maintaining tumor size; (4) reduction in tumor size; (5) inhibition,including (i) reduction, (ii) slowing down or (iii) complete prevention,of tumor cell infiltration into peripheral organs; (6) inhibition,including (i) reduction, (ii) slowing down or (iii) complete prevention,of metastasis; (7) enhancement of anti-tumor immune response, which mayresult in (i) maintaining tumor size, (ii) reducing tumor size, (iii)slowing the growth of a tumor, (iv) reducing, slowing or preventinginvasion and/or (8) relief, to some extent, of the severity or number ofone or more symptoms associated with the disorder.

The term “halo” refers to fluoro (F), chloro (Cl), bromo (Br), or iodo(I).

The term “alkyl” refers to a hydrocarbon chain that may be a straightchain or branched chain, containing the indicated number of carbonatoms. For example, C₁₋₁₀ indicates that the group may have from 1 to 10(inclusive) carbon atoms in it. Non-limiting examples include methyl,ethyl, iso-propyl, tert-butyl, n-hexyl.

The term “haloalkyl” refers to an alkyl, in which one or more hydrogenatoms is/are replaced with an independently selected halo.

The term “alkoxy” refers to an —O-alkyl radical (e.g., —OCH₃).

The term “alkylene” refers to a branched or unbranched divalent alkyl(e.g., —CH₂—).

The term “alkenyl” refers to a hydrocarbon chain that may be a straightchain or branched chain having one or more carbon-carbon double bonds.The alkenyl moiety contains the indicated number of carbon atoms. Forexample, C₂₋₆ indicates that the group may have from 2 to 6 (inclusive)carbon atoms in it.

The term “alkynyl” refers to a hydrocarbon chain that may be a straightchain or branched chain having one or more carbon-carbon triple bonds.The alkynyl moiety contains the indicated number of carbon atoms. Forexample, C₂₋₆ indicates that the group may have from 2 to 6 (inclusive)carbon atoms in it.

The term “aromatic” refers generally to a ring that includes a cyclicarray of resonance-stabilized 4n+2 pi electrons, wherein n is an integer(e.g., 1 or 2). Aromatic moieties include aryl and heteroaryl groups.The term “nonaromatic” describes any moiety that does not fall withinthe definition of “aromatic”.

The term “aryl” refers to a 6-carbon monocyclic, 10-carbon bicyclic, or14-carbon tricyclic aromatic ring system wherein 0, 1, 2, 3, or 4 atomsof each ring may be substituted by a substituent, and wherein the ringcomprising a monocyclic radical is aromatic and wherein at least one ofthe fused rings comprising a bicyclic or tricyclic radical is aromatice.g. tetrahydronaphthyl. Examples of aryl groups also include phenyl,naphthyl and the like.

The term “cycloalkyl” as used herein includes saturated cyclichydrocarbon groups having 3 to 10 carbons, preferably 3 to 8 carbons,and more preferably 3 to 6 carbons, wherein the cycloalkyl group may beoptionally substituted. Preferred cycloalkyl groups include, withoutlimitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. The term“cycloalkylene” as used herein refers to divalent cycloalkyl.

The term “heteroaryl” refers to an aromatic 5-8 membered monocyclic,8-12 membered bicyclic, or 11-14 membered tricyclic ring system having1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S(e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S ifmonocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2, 3,or 4 atoms of each ring may be substituted by a substituent, and whereinthe ring comprising a monocyclic radical is aromatic and wherein atleast one of the fused rings comprising a bicyclic or tricyclic radicalis aromatic (but does not have to be a ring which contains a heteroatom,e.g. tetrahydroisoquinolinyl. Examples of heteroaryl groups also includepyridyl, furyl or furanyl, imidazolyl, benzimidazolyl, pyrimidinyl,thiophenyl or thienyl, quinolinyl, indolyl, thiazolyl, and the like.

The term “heterocyclyl” refers to a nonaromatic 5-8 membered monocyclic,8-12 membered bicyclic, or 11-14 membered tricyclic ring system having1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, or S(e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S ifmonocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2 or 3atoms of each ring may be substituted by a substituent. Examples ofheterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl,morpholinyl, tetrahydrofuranyl, and the like. The term“heterocycloalkylene” refers to divalent heterocyclyl.

In addition, atoms making up the compounds of the present embodimentsare intended to include all isotopic forms of such atoms. Isotopes, asused herein, include those atoms having the same atomic number butdifferent mass numbers. By way of general example and withoutlimitation, isotopes of hydrogen include tritium and deuterium, andisotopes of carbon include ¹³C and ¹⁴C.

The details of one or more embodiments of the invention are set forth inthe accompanying drawings and the description below. Other features andadvantages of the invention will be apparent from the description anddrawings, and from the claims.

DETAILED DESCRIPTION

This disclosure features chemical entities (e.g., a compound or apharmaceutically acceptable salt, and/or hydrate, and/or cocrystal,and/or drug combination of the compound) that modulate (e.g., agonizesor partially agonizes) NLRP3 that are useful, e.g., for treating acondition, disease or disorder in which an increase in NLRP3 signalingmay correct a deficiency in innate immune activity (e.g., a condition,disease or disorder associated with an insufficient immune response)that contributes to the pathology and/or symptoms and/or progression ofthe condition, disease or disorder (e.g., cancer) in a subject (e.g., ahuman). This disclosure also features compositions as well as othermethods of using and making the same.

COMPOUNDS OF INVENTION

In one aspect, compounds of Formula I, or a pharmaceutically acceptablesalt thereof are featured:

W′ is R² or Q′-R²;

Q′ is NH, O, or S;

W is H, R², or Q-R²Q is NR¹, CHR¹, O, or S;R¹ is independently H or X—R⁵; wherein:

-   -   X is selected from: C₁₋₁₀ alkylene, C₂₋₁₀ alkenylene, and C₂₋₁₀        alkynylene, wherein each of which is optionally interrupted by        one O or S and/or each of which is optionally substituted with        from 1-4 R^(e);    -   R⁵ is selected from:    -   (i) hydrogen;    -   (ii) —OH;    -   (iii) C₁₋₄ alkoxy;    -   (iv) C₁₋₄ haloalkoxy;    -   (v) —CO₂R^(a);    -   (vi) —CONR′R″;    -   (vi) cyano;    -   (vii) —NR^(b)R^(c);    -   (viii) Q¹-aryl that is optionally substituted with from 1-3        R^(d);    -   (ix) Q¹-heteroaryl including from 5-6 ring atoms, wherein from        1-4 ring atoms are each independently selected from N, N(R^(f)),        O, and S, wherein the heteroaryl is optionally substituted with        from 1-3 R^(d);    -   (x) Q¹-C₃₋₁₀ cycloalkyl that is optionally substituted with from        1-4 R^(g),    -   (xi) Q¹-heterocyclyl including from 3-10 ring atoms, wherein        from 1-3 ring atoms are each independently selected from N,        N(R^(f)) and O, wherein the heterocyclyl is optionally        substituted with from 1-4 R^(g),    -   (xii) C₁₋₄ thioalkoxy;    -   (xiii) —SH    -   (xiv) —N₃;    -   (xv) —CO₂H;    -   (xvi) —C(O)R^(a); and    -   (xvii) —SO₁₋₂(R^(h));    -   Q¹ is selected from: a bond, O, —O(C₁₋₃ alkylene)-, S, and        —S(C₁₋₃ alkylene)-;        R² is selected from: H, R⁶, and -Q²-Y—R⁶;    -   Q² is selected from: a bond, C(O), N(R^(f)), O, and S;    -   Y is selected from: C₁₋₁₀ alkylene, C₂₋₁₀ alkenylene, and C₂₋₁₀        alkynylene, each of which is optionally substituted with from        1-4 R^(e) and/or each of which is optionally interrupted by one        or more of the following:        -   (i) O;        -   (ii) S;        -   (iii) N(R^(f));        -   (iv) C₃₋₆ cycloalkylene optionally substituted with from 1-4            R^(g),        -   (v) C₆₋₁₀ arylene, optionally further substituted with from            1-4 R^(d),        -   (vi) heteroarylene including from 5-10 ring atoms, wherein            from 1-4 ring atoms are each independently selected from N,            N(R^(f)), O, and S, and which is optionally substituted with            from 1-4 R^(g), or        -   (vii) heterocycloalkylene including from 3-10 ring atoms,            wherein from 1-3 ring atoms are each independently selected            from N, N(R^(f)) and O, and which is optionally further            substituted with from 1-4 R^(g), and    -   R⁶ is selected from:    -   (i) hydrogen;    -   (ii) —OH;    -   (iii) C₁₋₄ alkoxy;    -   (iv) C₁₋₄ haloalkoxy;    -   (v) —CO₂R^(a);    -   (vi) —CONR′R″;    -   (vi) cyano;    -   (vii) —NR^(b)R^(c);    -   (viii) Q¹-aryl that is optionally substituted with from 1-3        R^(d);    -   (ix) Q¹-heteroaryl including from 5-10 ring atoms, wherein from        1-4 ring atoms are each independently selected from N, N(R^(f)),        O, and S, wherein the heteroaryl is optionally substituted with        from 1-3 R^(d);    -   (x) Q¹-C₃₋₁₀ cycloalkyl that is optionally substituted with from        1-4 R^(g),    -   (xi) Q¹-heterocyclyl including from 3-10 ring atoms, wherein        from 1-3 ring atoms are each independently selected from N,        N(R^(f)) and O, wherein the heterocyclyl is optionally        substituted with from 1-4 R^(g),    -   (xii) C₁₋₄ thioalkoxy;    -   (xiii) —SH    -   (xiv) —N₃;    -   (xv) —CO₂H;    -   (xvi) —C(O)R^(a); and    -   (xvii) —SO₁₋₂(R^(h));        R³ and R⁴ are each independently selected from:        (i) hydrogen;        (ii) halo;        (iii) cyano;        (iv) —CO₂R^(a);

(v) —CONR′R″;

(vi) C₁₋₄ alkyl, optionally substituted with from 1-2 independentlyselected R^(e);(vii) C₁₋₄ haloalkyl;(viii) C₁₋₄ alkoxy;(ix) C₁₋₄ haloalkoxy;(x) Y⁴—(C₁₋₃ alkylene)_(y)-C₅₋₈ cycloalkyl, wherein the cycloalkyl isoptionally substituted with from 1-4 independently selected R^(g),wherein y is 0 or 1; and Y⁴ is a bond, N(R^(f)), O, or S;(xi) Y⁴—(C₁₋₃ alkylene)_(y)-heterocyclyl including from 5-8 ring atoms,wherein from 1-3 ring atoms are each independently selected fromN(R^(f)), O, and S, wherein the heterocyclyl is optionally substitutedwith from 1-4 independently selected R^(g), wherein y is 0 or 1; and Y⁴is a bond, N(R^(f)), O, or S;(xii) Y⁴—(C₁₋₃ alkylene)_(y)-C₆₋₁₀ aryl optionally substituted with from1-4 R^(d), wherein y is 0 or 1; and Y⁴ is a bond, N(R^(f)), O, or S;(xiii) Y⁴—(C₁₋₃ alkylene)_(y)-heteroaryl including from 5-10 ring atoms,wherein from 1-4 ring atoms are each independently selected from N,N(R^(f)), O, and S, wherein the heteroaryl is optionally substitutedwith from 1-3 R^(d), wherein y is 0 or 1; and Y⁴ is a bond, N(R^(f)), O,or S;(xiv) —N₃;

(xv) —CO₂H;

(xvi) —OH;(xvii) —SO₁₋₂(R^(h));(xviii) —NR^(b)R^(c);(xvix) —SO₁₋₂(NR′R″); and(xx) thioalkoxy;

R^(a) is:

-   -   (i) C₁₋₈ alkyl optionally substituted with from 1-2        independently selected R^(e);    -   (ii) —(C₀₋₆ alkylene)-C₃₋₁₀ cycloalkyl, wherein the cycloalkyl        is optionally substituted with from 1-4 independently selected        R^(g);    -   (iii) —(C₀₋₆ alkylene)-heterocyclyl including from 3-10 ring        atoms, wherein from 1-3 ring atoms are each independently        selected from N(R^(f)), O, and S, wherein the heterocyclyl is        optionally substituted with from 1-4 independently selected        R^(g);    -   (iv) —(C₀₋₆ alkylene)-(C₆₋₁₀ aryl), wherein the aryl is        optionally substituted with from 1-5 independently selected        R^(d); or    -   (v) —(C₀₋₆ alkylene)-heteroaryl including from 5-10 ring atoms,        wherein from 1-4 ring atoms are each independently selected from        N, N(R^(f)), O, and S, wherein the heteroaryl is optionally        substituted with from 1-3 independently selected R^(d);        each occurrence of R^(b) and R^(c) is independently selected        from: H; R^(a); —C(O)(R^(a)), —C(O)O(R^(a)), —S(O)₁₋₂(R^(h)),        —C(O)NR′R″, —S(O)₁₋₂(NR′R″), —OH, and C₁₋₄ alkoxy;        each occurrence of R^(d) is independently selected from:        (i) halo;        (ii) cyano;        (iii) C₁₋₆ alkyl optionally substituted with from 1-2        independently selected R^(e);        (iv) C₂₋₆ alkenyl;        (v) C₂₋₆ alkynyl;        (vi) C₁₋₄ haloalkyl;        (vii) C₁₋₄ alkoxy;        (viii) C₁₋₄ haloalkoxy;        (ix) —(C₀₋₃ alkylene)-C₃₋₆ cycloalkyl optionally substituted        with from 1-4 independently selected C₁₋₄ alkyl;        (x) —(C₀₋₃ alkylene)-heterocyclyl including from 3-10 ring        atoms, wherein from 1-3 ring atoms are each independently        selected from N(R^(f)), O, and S, wherein the heterocyclyl is        optionally substituted with from 1-4 independently selected C₁₋₄        alkyl;        (xi) —(C₀₋₃ alkylene)-phenyl optionally substituted with from        1-3 R^(m);        (xii) —(C₀₋₃ alkylene)-heteroaryl including from 5-10 ring        atoms, wherein from 1-4 ring atoms are each independently        selected from N, N(R^(f)), O, and S, wherein the heteroaryl is        optionally substituted with from 1-3 R^(m);        (xiii) —S(O)₁₋₂(R^(h)); and        (xiv) —NR^(j)R^(k);

(xv) —OH;

(xvi) —S(O)₁₋₂(NR′R″);(xvii) —C₁₋₄ thioalkoxy;(xviii) —NO₂;(xix) —N(R^(n))(C(═O)C₁₋₃ alkyl);(xx) —C(═O)(C₁₋₄ alkyl);(xxi) —C(═O)O(C₁₋₄ alkyl);(xxii) —C(═O)OH, and(xxiii) —C(═O)N(R′)(R″);each occurrence of R^(e) is independently selected from: —OH; F;—NR^(j)R^(k); —N(R^(n))(C(═O)C₁₋₄ alkyl); —N(R^(n))(C(═O)OC₁₋₄ alkyl);C₁₋₄ alkoxy; C₁₋₄ haloalkoxy; —C(═O)O(C₁₋₄ alkyl); —C(═O)(C₁₋₄ alkyl);—C(═O)OH; —CON(R′)(R″); —S(O)₁₋₂(NR′R″); —S(O)₁₋₂(C₁₋₄ alkyl); andcyano;each occurrence of R^(f) is independently selected from: H; C₁₋₄ alkyl;C₃₋₆ cycloalkyl; phenyl; —C(O)(C₁₋₄ alkyl); —C(O)O(C₁₋₄ alkyl);—CON(R′)(R″); —S(O)₁₋₂(NR′R″); —S(O)₁₋₂R^(h); —OH; and C₁₋₄ alkoxy;wherein each C₁₋₄ alkyl is optionally substituted with from 1-2independently selected R^(e); each C₃₋₆ cycloalkyl is optionallysubstituted with from 1-2 independently selected R^(g); and each phenylis optionally substituted with from 1-2 independently selected R^(d);each occurrence of R^(g) is independently selected from: C₁₋₆ alkyloptionally substituted with from 1-2 independently selected R; C₁₋₄haloalkyl; —OH; oxo; F; Cl; Br; —NR^(j)R^(k); —N(R^(n))(C(═O)C₁₋₄alkyl); C₁₋₄ alkoxy; C₁₋₄ haloalkoxy; —C(═O)(C₁₋₄ alkyl); —C(═O)O(C₁₋₄alkyl); —C(═O)OH; —C(═O)N(R′)(R″); —S(O)₁₋₂(NR′R″); —S(O)₁₋₂(C₁₋₄alkyl); cyano; C₃₋₆ cycloalkyl optionally substituted with from 1-4independently selected C₁₋₄ alkyl; heteroaryl including from 5-10 ringatoms, wherein from 1-4 ring atoms are each independently selected fromN, N(R^(f)), O, and S, wherein the heteroaryl is optionally substitutedwith from 1-3 R^(m); and phenyl optionally substituted with from 1-4R^(m);each occurrence of R^(h) is independently selected from: C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, phenyl optionallysubstituted with from 1-3 R^(m), and heteroaryl including from 5-6 ringatoms, wherein from 1-4 ring atoms are each independently selected fromN, N(R^(f)), O, and S, wherein the heteroaryl is optionally substitutedwith from 1-3 R^(m);each occurrence of R^(j) and R^(k) is independently selected from: H andC₁₋₄ alkyl, which is optionally substituted with from 1-2 independentlyselected R^(u), wherein each occurrence of R^(u) is independentlyselected from: —OH, —N(R^(p))R^(q)), —N(R^(n))(C(═O)C₁₋₄ alkyl),—N(R^(n))(C(═O)OC₁₋₄ alkyl), C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, —C(═O)(C₁₋₄alkyl); —C(═O)O(C₁₋₄ alkyl); —C(═O)OH; —C(═O)N(R^(p))(R^(q)),—S(O)₁₋₂(C₁₋₄ alkyl); —S(O)₁₋₂(N(R^(p))(R^(q))), and cyano;each occurrence of R^(m) is independently selected from: C₁₋₄ alkyl;C₁₋₄ haloalkyl; —OH, F, Cl, Br, —N(R^(j))(R^(k)), —N(R^(n))(C(═O)C₁₋₄alkyl), —N(R^(n))(C(═O)OC₁₋₄ alkyl), C₁₋₄ alkoxy, C₁₋₄ haloalkoxy,—C(═O)(C₁₋₄ alkyl); —C(═O)O(C₁₋₄ alkyl); —C(═O)OH,—C(═O)N(R^(p))(R^(q)), —S(O)₁₋₂(C₁₋₄ alkyl); —S(O)₁₋₂(N(R^(p))(R^(q))),and cyano;each occurrence of R^(n), R^(p), and R^(q) is independently selectedfrom: H and C₁₋₄ alkyl;each occurrence of R′ and R″ is independently selected from: H and C₁₋₄alkyl, which is optionally substituted with from 1-2 independentlyselected R^(u); or R′ and R″ together with the nitrogen atom to whicheach is attached forms a ring including from 3-8 ring atoms, wherein thering includes: (a) from 1-7 ring carbon atoms, each of which issubstituted with from 1-2 substituents independently selected from H andR^(s); and (b) from 0-3 ring heteroatoms (in addition to the nitrogenatom attached to R′ and R″), which are each independently selected fromN(R^(t)), O, and S;each occurrence of R^(s) is independently selected from: C₁₋₆ alkyloptionally substituted with from 1-2 independently selected R^(u); C₁₋₄haloalkyl; —OH; oxo; F; Cl; Br; —NR^(j)R^(k); —N(R^(n))(C(═O)C₁₋₄alkyl); C₁₋₄ alkoxy; C₁₋₄ haloalkoxy; —C(═O)(C₁₋₄ alkyl); —C(═O)O(C₁₋₄alkyl); —C(═O)OH; —C(═O)N(R^(p))(R^(q)); —S(O)₁₋₂(N(R^(p))(R^(q)));—S(O)₁₋₂(C₁₋₄ alkyl); cyano; heteroaryl including from 5-10 ring atoms,wherein from 1-4 ring atoms are each independently selected from N,N(R^(f)), O, and S, wherein the heteroaryl is optionally substitutedwith from 1-3 R^(m); phenyl optionally substituted with from 1-4 R^(m);and C₃₋₆ cycloalkyl optionally substituted with from 1-4 independentlyselected R^(u); andeach occurrence of R^(t) is independently selected from: H; C₁₋₄ alkyl;C₃₋₆ cycloalkyl; phenyl; —C(O)(C₁₋₄ alkyl); —C(O)O(C₁₋₄ alkyl);—CON(R^(p))(R^(q)); —S(O)₁₋₂(N(R^(p))(R^(q))), —S(O)₁₋₂R^(h); —OH; andC₁₋₄ alkoxy; wherein each C₁₋₄ alkyl is optionally substituted with from1-2 independently selected R^(u); each C₃₋₆ cycloalkyl is optionallysubstituted with from 1-4 independently selected R^(s); and each phenylis optionally substituted with from 1-2 independently selected R^(m).

In some embodiments, it is provided that at least one of R³ and R⁴ is asubstituent other than H.

In one aspect, compounds of Formula I, or a pharmaceutically acceptablesalt thereof are featured:

W′ is R² or Q′-R²;

Q′ is NH, O, or S;

W is H, R², or Q-R²Q is NR¹, CHR¹, O, or S;

R¹ is: (i) H

(ii) X—R⁵, wherein X is an unbranched C₁₋₆ alkylene, and R⁵ is hydrogen,—OH, C₁₋₄ alkoxy, —C₁₋₄ haloalkoxy, CO₂R^(a), —CONR′R″, cyano, or—NR^(b)R^(c);(iii) (C₁₋₃ alkylene)-aryl, wherein the aryl is optionally substitutedwith from 1-3 R^(d); or(iv) (C₁₋₃ alkylene)-heteroaryl including from 5-6 ring atoms, whereinfrom 1-4 ring atoms are each independently selected from N, N(R^(f)), O,and S, wherein the heteroaryl is optionally substituted with from 1-3R^(d);

R² is:

(i) —Y—R⁶, wherein

-   -   Y is C₁₋₈ alkylene, which is optionally substituted with from        1-4 R^(e); and    -   R⁶ is —OH, —O(C₁₋₄ alkyl), —C(O)R^(a), —CO₂R^(a), —CONR′R″,        —NR^(b)R^(c), cyano, aryl that is optionally substituted with        from 1-3 independently selected R^(d); or heteroaryl including        from 5-6 ring atoms, wherein from 1-4 ring atoms are each        independently selected from N, N(R^(f)), O, and S, wherein the        heteroaryl is optionally substituted with from 1-3 R^(d);

OR (ii) —C(O)—Y—R⁶; OR

(iii) —R⁶;

OR

(iv) —(Y¹)_(n)—Y²—(Y³)_(p)—R^(6′), wherein:

-   -   each of n and p is independently 0 or 1;    -   each of Y¹ and Y³ is, independently, C₁₋₃ alkylene, which is        optionally substituted with from 1-2 R^(e),    -   Y² is:        -   (a) C₃₋₆ cycloalkylene optionally substituted with from 1-4            R^(g),        -   (b) C₆₋₁₀ arylene, optionally further substituted with from            1-4 R^(d),        -   (c) heteroarylene including from 5-10 ring atoms, wherein            from 1-4 ring atoms are each independently selected from N,            N(R^(f)), O, and S, and which is optionally further            substituted with from 1-4 R^(g), or        -   (d) heterocycloalkylene including from 3-10 ring atoms,            wherein from 1-3 ring atoms are each independently selected            from N, N(R^(f)) and O, and wherein Y² is optionally further            substituted with from 1-4 R^(g), and    -   R^(6′) is H, —OH, —C(O)R^(a), —CO₂R^(a); —CONR′R″, —NR^(b)R^(c),        cyano, or heteroaryl including from 5-6 ring atoms, wherein from        1-4 ring atoms are each independently selected from N, N(R^(f)),        O, and S, in some embodiments R^(6′) cannot be H when Y² is C₃₋₆        cycloalkylene optionally substituted with from 1-4 R^(g) and/or        when Y² is C₆₋₁₀ arylene, optionally substituted with from 1-4        R^(d),

OR

(v) —Z¹—Z²—Z³—R⁷, wherein:

-   -   Z¹ is C₁₋₃ alkylene, which is optionally substituted with from        1-6 F,    -   Z² is —N(R^(f))—, —O—, or —S—;    -   Z³ is C₂₋₅ alkylene, which is optionally substituted with from        1-6 F, and    -   R⁷ is —OH, —C(O)R^(a), CO₂R^(a); —CONR′R″, —NR^(b)R^(c), or        heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring        atoms are each independently selected from N, N(R^(f)), O, and        S, wherein the heteroaryl is optionally substituted with from        1-3 R^(d);        R³ and R⁴ are each independently selected from:        (i) hydrogen;        (ii) halo;        (iii) cyano;        (iv) —CO₂R^(a);

(v) —CONR′R″;

(vi) C₁₋₄ alkyl, optionally substituted with from 1-2 independentlyselected R^(e);(vii) C₁₋₄ haloalkyl;(viii) C₁₋₄ alkoxy;(ix) C₁₋₄ haloalkoxy;(x) Y⁴—(C₁₋₃ alkylene)_(y)-C₅₋₈ cycloalkyl, wherein the cycloalkyl isoptionally substituted with from 1-4 independently selected R^(g),wherein y is 0 or 1; and Y⁴ is a bond, N(R^(f)), O, or S;(xi) Y⁴—(C₁₋₃ alkylene)_(y)-heterocyclyl including from 5-8 ring atoms,wherein from 1-3 ring atoms are each independently selected fromN(R^(f)), O, and S, wherein the heterocyclyl is optionally substitutedwith from 1-4 independently selected R^(g), wherein y is 0 or 1; and Y⁴is a bond, N(R^(f)), O, or S;(xii) Y⁴—(C₁₋₃ alkylene)_(y)-C₆₋₁₀ aryl optionally substituted with from1-4 R^(d), wherein y is 0 or 1; and Y⁴ is a bond, N(R^(f)), O, or S;(xiii) Y⁴—(C₁₋₃ alkylene)_(y)-heteroaryl including from 5-10 ring atoms,wherein from 1-4 ring atoms are each independently selected from N,N(R^(f)), O, and S, wherein the heteroaryl is optionally substitutedwith from 1-3 R^(d), wherein y is 0 or 1; and Y⁴ is a bond, N(R^(f)), O,or S;(xiv) —N₃;

(xv) —CO₂H;

(xvi) —OH;(xvii) —SO₁₋₂(R^(h));(xviii) —NR^(b)R^(c);(xvix) —SO₁₋₂(NR′R″); and(xx) thioalkoxy;

R^(a) is:

-   -   (i) C₁₋₈ alkyl optionally substituted with from 1-2        independently selected R^(e);    -   (ii) —(C₀₋₆ alkylene)-C₃₋₁₀ cycloalkyl, wherein the cycloalkyl        is optionally substituted with from 1-4 independently selected        R^(g);    -   (iii) —(C₀₋₆ alkylene)-heterocyclyl including from 3-10 ring        atoms, wherein from 1-3 ring atoms are each independently        selected from N(R^(f)), O, and S, wherein the heterocyclyl is        optionally substituted with from 1-4 independently selected        R^(g);    -   (iv) —(C₀₋₆ alkylene)-(C₆₋₁₀ aryl), wherein the aryl is        optionally substituted with from 1-5 independently selected        R^(d); or    -   (v) —(C₀₋₆ alkylene)-heteroaryl including from 5-10 ring atoms,        wherein from 1-4 ring atoms are each independently selected from        N, N(R^(f)), O, and S, wherein the heteroaryl is optionally        substituted with from 1-3 independently selected R^(d);        each occurrence of R^(b) and R^(c) is independently selected        from: H; R^(a); —C(O)(R^(a)), —C(O)O(R^(a)), —S(O)₁₋₂(R^(h)),        —C(O)NR′R″, —S(O)₁₋₂(NR′R″), —OH, and C₁₋₄ alkoxy;        each occurrence of R^(d) is independently selected from:        (i) halo;        (ii) cyano;        (iii) C₁₋₆ alkyl optionally substituted with from 1-2        independently selected R^(e);        (iv) C₂₋₆ alkenyl;        (v) C₂₋₆ alkynyl;        (vi) C₁₋₄ haloalkyl;        (vii) C₁₋₄ alkoxy;        (viii) C₁₋₄ haloalkoxy;        (ix) —(C₀₋₃ alkylene)-C₃₋₆ cycloalkyl optionally substituted        with from 1-4 independently selected C₁₋₄ alkyl;        (x) —(C₀₋₃ alkylene)-heterocyclyl including from 3-10 ring        atoms, wherein from 1-3 ring atoms are each independently        selected from N(R^(f)), O, and S, wherein the heterocyclyl is        optionally substituted with from 1-4 independently selected C₁₋₄        alkyl;        (xi) —(C₀₋₃ alkylene)-phenyl optionally substituted with from        1-3 R^(m);        (xii) —(C₀₋₃ alkylene)-heteroaryl including from 5-10 ring        atoms, wherein from 1-4 ring atoms are each independently        selected from N, N(R^(f)), O, and S, wherein the heteroaryl is        optionally substituted with from 1-3 R^(m);        (xiii) —S(O)₁₋₂(R^(h)); and        (xiv) —NR^(j)R^(k);

(xv) —OH;

(xvi) —S(O)₁₋₂(NR′R″);(xvii) —C₁₋₄ thioalkoxy;(xviii) —NO₂;(xix) —N(R^(n))(C(═O)C₁₋₃ alkyl);(xx) —C(═O)(C₁₋₄ alkyl);(xxi) —C(═O)O(C₁₋₄ alkyl);(xxii) —C(═O)OH, and(xxiii) —C(═O)N(R′)(R″);each occurrence of R^(e) is independently selected from: —OH; F;—NR^(j)R^(k); —N(R^(n))(C(═O)C₁₋₄ alkyl); —N(R^(n))(C(═O)OC₁₋₄ alkyl);C₁₋₄ alkoxy; C₁₋₄ haloalkoxy; —C(═O)O(C₁₋₄ alkyl); —C(═O)(C₁₋₄ alkyl);—C(═O)OH; —CON(R′)(R″); —S(O)₁₋₂(NR′R″); —S(O)₁₋₂(C₁₋₄ alkyl); andcyano;each occurrence of R^(f) is independently selected from: H; C₁₋₄ alkyl;C₃₋₆ cycloalkyl; phenyl; —C(O)(C₁₋₄ alkyl); —C(O)O(C₁₋₄ alkyl);—CON(R′)(R″); —S(O)₁₋₂(NR′R″); —S(O)₁₋₂R^(h); —OH; and C₁₋₄ alkoxy;wherein each C₁₋₄ alkyl is optionally substituted with from 1-2independently selected R^(e); each C₃₋₆ cycloalkyl is optionallysubstituted with from 1-2 independently selected R^(g); and each phenylis optionally substituted with from 1-2 independently selected R^(d);each occurrence of R^(g) is independently selected from: C₁₋₆ alkyloptionally substituted with from 1-2 independently selected R^(e); C₁₋₄haloalkyl; —OH; oxo; F; Cl; Br; —NR^(j)R^(k); —N(R^(n))(C(═O)C₁₋₄alkyl); C₁₋₄ alkoxy; C₁₋₄ haloalkoxy; —C(═O)(C₁₋₄ alkyl); —C(═O)O(C₁₋₄alkyl); —C(═O)OH; —C(═O)N(R′)(R″); —S(O)₁₋₂(NR′R″); —S(O)₁₋₂(C₁₋₄alkyl); cyano; C₃₋₆ cycloalkyl optionally substituted with from 1-4independently selected C₁₋₄ alkyl; heteroaryl including from 5-10 ringatoms, wherein from 1-4 ring atoms are each independently selected fromN, N(R^(f)), O, and S, wherein the heteroaryl is optionally substitutedwith from 1-3 R^(m); and phenyl optionally substituted with from 1-4R^(m);each occurrence of R^(h) is independently selected from: C₁₋₆ alkyl,C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, phenyl optionallysubstituted with from 1-3 R^(m), and heteroaryl including from 5-6 ringatoms, wherein from 1-4 ring atoms are each independently selected fromN, N(R^(f)), O, and S, wherein the heteroaryl is optionally substitutedwith from 1-3 R^(m);each occurrence of R^(j) and R^(k) is independently selected from: H andC₁₋₄ alkyl, which is optionally substituted with from 1-2 independentlyselected R^(u), wherein each occurrence of R^(u) is independentlyselected from: —OH, —N(R^(p))(R^(q)), —N(R^(n))(C(═O)C₁₋₄ alkyl),—N(R^(n))(C(═O)OC₁₋₄ alkyl), C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, —C(═O)(C₁₋₄alkyl); —C(═O)O(C₁₋₄ alkyl); —C(═O)OH; —C(═O)N(R^(p))(R^(q)),—S(O)₁₋₂(C₁₋₄ alkyl); —S(O)₁₋₂(N(R^(p))(R^(q))), and cyano;each occurrence of R^(m) is independently selected from: C₁₋₄ alkyl;C₁₋₄ haloalkyl; —OH, F, Cl, Br, —N(R^(j))(R^(k)), —N(R^(n))(C(═O)C₁₋₄alkyl), —N(R^(n))(C(═O)OC₁₋₄ alkyl), C₁₋₄ alkoxy, C₁₋₄ haloalkoxy,—C(═O)(C₁₋₄ alkyl); —C(═O)O(C₁₋₄ alkyl); —C(═O)OH,—C(═O)N(R^(p))(R^(q)), —S(O)₁₋₂(C₁₋₄ alkyl); —S(O)₁₋₂(N(R^(p))(R^(q))),and cyano;each occurrence of R^(n), R^(p), and R^(q) is independently selectedfrom: H and C₁₋₄ alkyl;each occurrence of R′ and R″ is independently selected from: H and C₁₋₄alkyl, which is optionally substituted with from 1-2 independentlyselected R^(u); or R′ and R″ together with the nitrogen atom to whicheach is attached forms a ring including from 3-8 ring atoms, wherein thering includes: (a) from 1-7 ring carbon atoms, each of which issubstituted with from 1-2 substituents independently selected from H andR^(s); and (b) from 0-3 ring heteroatoms (in addition to the nitrogenatom attached to R′ and R″), which are each independently selected fromN(R^(t)), O, and S;each occurrence of R^(s) is independently selected from: C₁₋₆ alkyloptionally substituted with from 1-2 independently selected R^(u); C₁₋₄haloalkyl; —OH; oxo; F; Cl; Br; —NR^(j)R^(k); —N(R^(n))(C(═O)C₁₋₄alkyl); C₁₋₄ alkoxy; C₁₋₄ haloalkoxy; —C(═O)(C₁₋₄ alkyl); —C(═O)O(C₁₋₄alkyl); —C(═O)OH; —C(═O)N(R^(p))(R^(q)); —S(O)₁₋₂(N(R^(p))(R^(q)));—S(O)₁₋₂(C₁₋₄ alkyl); cyano; heteroaryl including from 5-10 ring atoms,wherein from 1-4 ring atoms are each independently selected from N,N(R^(f)), O, and S, wherein the heteroaryl is optionally substitutedwith from 1-3 R^(m); phenyl optionally substituted with from 1-4 R^(m);and C₃₋₆ cycloalkyl optionally substituted with from 1-4 independentlyselected R^(u); andeach occurrence of R^(t) is independently selected from: H; C₁₋₄ alkyl;C₃₋₆ cycloalkyl; phenyl; —C(O)(C₁₋₄ alkyl); —C(O)O(C₁₋₄ alkyl);—CON(R^(p))(R^(q)); —S(O)₁₋₂(N(R^(p))(R^(q))), —S(O)₁₋₂R^(h); —OH; andC₁₋₄ alkoxy; wherein each C₁₋₄ alkyl is optionally substituted with from1-2 independently selected R^(u); each C₃₋₆ cycloalkyl is optionallysubstituted with from 1-4 independently selected R^(s); and each phenylis optionally substituted with from 1-2 independently selected R^(m).

In one aspect, compounds of Formula I, or a pharmaceutically acceptablesalt thereof are featured:

W′ is R² or Q′-R²

Q′ is NH, O, or S;

W is H, R², or Q-R²Q is NR¹, CHR¹, O, or S;R¹ is independently H or X—R⁵; wherein:

-   -   X is selected from: C₁₋₁₀ alkylene, C₂₋₁₀ alkenylene, and C₂₋₁₀        alkynylene, wherein each of which is optionally interrupted by        one O or S and/or each of which is optionally substituted with        from 1-4 R^(e);    -   R⁵ is selected from:    -   (i) hydrogen;    -   (ii) —OH;    -   (iii) C₁₋₄ alkoxy;    -   (iv) C₁₋₄ haloalkoxy;    -   (v) —CO₂R^(a);    -   (vi) —CONR′R″;    -   (vi) cyano;    -   (vii) —NR^(b)R^(c);    -   (viii) Q¹-aryl that is optionally substituted with from 1-3        R^(d);    -   (ix) Q¹-heteroaryl including from 5-6 ring atoms, wherein from        1-4 ring atoms are each independently selected from N, N(R^(f)),        O, and S, wherein the heteroaryl is optionally substituted with        from 1-3 R^(d);    -   (x) Q¹-C₃₋₁₀ cycloalkyl that is optionally substituted with from        1-4 R^(g),    -   (xi) Q¹-heterocyclyl including from 3-10 ring atoms, wherein        from 1-3 ring atoms are each independently selected from N,        N(R^(f)) and O, wherein the heterocyclyl is optionally        substituted with from 1-4 R^(g),    -   (xii) C₁₋₄ thioalkoxy;    -   (xiii) —SH    -   (xiv) —N₃;    -   (xv) —CO₂H;    -   (xvi) —C(O)R^(a); and    -   (xvii) —SOI-2(R^(h))    -   Q¹ is independently selected from: a bond, O, —O(C₁₋₃        alkylene)-, S, and —S(C₁₋₃ alkylene)-;        R² is independently selected from: H, R⁶, and -Q²-Y—R⁶;    -   Q² is selected from: a bond, C(O), N(R^(f)), O, and S;    -   Y is selected from: C₁₋₁₀ alkylene, C₂₋₁₀ alkenylene, and C₂₋₁₀        alkynylene, each of which is optionally substituted with from        1-4 R^(e) and/or each of which is optionally interrupted by one        or more of the following:        -   (i) O;        -   (ii) S;        -   (iii) N(R^(f));        -   (iv) C₃₋₆ cycloalkylene optionally substituted with from 1-4            R^(g),        -   (v) C₆₋₁₀ arylene, optionally further substituted with from            1-4 R^(d),        -   (vi) heteroarylene including from 5-10 ring atoms, wherein            from 1-4 ring atoms are each independently selected from N,            N(R^(f)), O, and S, and which is optionally substituted with            from 1-4 R^(g), or        -   (vii) heterocycloalkylene including from 3-10 ring atoms,            wherein from 1-3 ring atoms are each independently selected            from N, N(R^(f)), O and S(O)₁₋₂, and which is optionally            further substituted with from 1-4 R^(g), and    -   R⁶ is independently selected from:    -   (i) hydrogen;    -   (ii) —OH;    -   (iii) C₁₋₄ alkoxy;    -   (iv) C₁₋₄ haloalkoxy;    -   (v) —CO₂R^(a);    -   (vi) —CONR′R″;    -   (vi) cyano;    -   (vii) —NR^(b)R^(c);    -   (viii) Q¹-aryl that is optionally substituted with from 1-3        R^(d);    -   (ix) Q¹-heteroaryl including from 5-10 ring atoms, wherein from        1-4 ring atoms are each independently selected from N, N(R^(f)),        O, and S, wherein the heteroaryl is optionally substituted with        from 1-3 R^(d);    -   (x) Q¹-C₃₋₁₀ cycloalkyl that is optionally substituted with from        1-4 R^(g),    -   (xi) Q¹-heterocyclyl including from 3-10 ring atoms, wherein        from 1-3 ring atoms are each independently selected from N,        N(R^(f)) and O, wherein the heterocyclyl is optionally        substituted with from 1-4 R^(g),    -   (xii) C₁₋₄ thioalkoxy;    -   (xiii) —SH    -   (xiv) —N₃;    -   (xv) —CO₂H;    -   (xvi) —C(O)R^(a); and    -   (xvii) —SO₁₋₂(R^(h));        R³ and R⁴ are each independently selected from:        (i) hydrogen;        (ii) halo;        (iii) cyano;        (iv) —CO₂R^(a);

(v) —CONR′R″;

(vi) C₁₋₄ alkyl, optionally substituted with from 1-2 independentlyselected R^(e);(vii) C₁₋₄ haloalkyl;(viii) C₁₋₄ alkoxy;(ix) C₁₋₄ haloalkoxy;(x) Y⁴—(C₁₋₃ alkylene)_(y)-C₅₋₈ cycloalkyl, wherein the cycloalkyl isoptionally substituted with from 1-4 independently selected R^(g),wherein y is 0 or 1; and Y⁴ is a bond, N(R^(f)), O, or S;(xi) Y⁴—(C₁₋₃ alkylene)_(y)-heterocyclyl including from 5-8 ring atoms,wherein from 1-3 ring atoms are each independently selected fromN(R^(f)), O, and S, wherein the heterocyclyl is optionally substitutedwith from 1-4 independently selected R^(g), wherein y is 0 or 1; and Y⁴is a bond, N(R^(f)), O, or S;(xii) Y⁴—(C₁₋₃ alkylene)_(y)-C₆₋₁₀ aryl optionally substituted with from1-4 R^(d), wherein y is 0 or 1; and Y⁴ is a bond, N(R^(f)), O, or S;(xiii) Y⁴—(C₁₋₃ alkylene)_(y)-heteroaryl including from 5-10 ring atoms,wherein from 1-4 ring atoms are each independently selected from N,N(R^(f)), O, and S, wherein the heteroaryl is optionally substitutedwith from 1-3 R^(d), wherein y is 0 or 1; and Y⁴ is a bond, N(R^(f)), O,or S;(xiv) —N₃;

(xv) —CO₂H;

(xvi) —OH;(xvii) —SO₁₋₂(R^(h));(xviii) —NR^(b)R^(c);(xvix) —SO₁₋₂(NR′R″); and(xx) thioalkoxy;

R^(a) is:

-   -   (i) C₁₋₈ alkyl optionally substituted with from 1-2        independently selected R;    -   (ii) —(C₀₋₆ alkylene)-C₃₋₁₀ cycloalkyl, wherein the cycloalkyl        is optionally substituted with from 1-4 independently selected        R^(g);    -   (iii) —(C₀₋₆ alkylene)-heterocyclyl including from 3-10 ring        atoms, wherein from 1-3 ring atoms are each independently        selected from N(R^(f)), O, and S, wherein the heterocyclyl is        optionally substituted with from 1-4 independently selected        R^(g);    -   (iv) —(C₀₋₆ alkylene)-(C₆₋₁₀ aryl), wherein the aryl is        optionally substituted with from 1-5 independently selected        R^(d); or    -   (v) —(C₀₋₆ alkylene)-heteroaryl including from 5-10 ring atoms,        wherein from 1-4 ring atoms are each independently selected from        N, N(R^(f)), O, and S, wherein the heteroaryl is optionally        substituted with from 1-3 independently selected R^(d);        each occurrence of R^(b) and R^(c) is independently selected        from: H; R^(a); —C(O)(R^(a)), —C(O)O(R^(a)), —S(O)₁₋₂(R^(h)),        —C(O)NR′R″, —S(O)₁₋₂(NR′R″), —OH, and C₁₋₄ alkoxy;        each occurrence of R^(d) is independently selected from:        (i) halo;        (ii) cyano;        (iii) C₁₋₆ alkyl optionally substituted with from 1-2        independently selected R^(e);        (iv) C₂₋₆ alkenyl;        (v) C₂₋₆ alkynyl;        (vi) C₁₋₄ haloalkyl;        (vii) C₁₋₄ alkoxy;        (viii) C₁₋₄ haloalkoxy;        (ix) —(C₀₋₃ alkylene)-C₃₋₆ cycloalkyl optionally substituted        with from 1-4 independently selected C₁₋₄ alkyl;        (x) —(C₀₋₃ alkylene)-heterocyclyl including from 3-10 ring        atoms, wherein from 1-3 ring atoms are each independently        selected from N(R^(f)), O, and S, wherein the heterocyclyl is        optionally substituted with from 1-4 independently selected C₁₋₄        alkyl;        (xi) —(C₀₋₃ alkylene)-phenyl optionally substituted with from        1-3 R^(m);        (xii) —(C₀₋₃ alkylene)-heteroaryl including from 5-10 ring        atoms, wherein from 1-4 ring atoms are each independently        selected from N, N(R^(f)), O, and S, wherein the heteroaryl is        optionally substituted with from 1-3 R^(m);        (xiii) —S(O)₁₋₂(R^(h)); and        (xiv) —NR^(j)R^(k);

(xv) —OH;

(xvi) —S(O)₁₋₂(NR′R″);(xvii) —C₁₋₄ thioalkoxy;(xviii) —NO₂;(xix) —N(R^(n))(C(═O)C₁₋₃ alkyl);(xx) —C(═O)(C₁₋₄ alkyl);(xxi) —C(═O)O(C₁₋₄ alkyl);(xxii) —C(═O)OH, and(xxiii) —C(═O)N(R′)(R″);each occurrence of R^(e) is independently selected from: —OH; F;—NR^(j)R^(k); —N(R^(n))(C(═O)C₁₋₄ alkyl); —N(R^(n))(C(═O)OC₁₋₄ alkyl);C₁₋₄ alkoxy; C₁₋₄ haloalkoxy; —C(═O)O(C₁₋₄ alkyl); —C(═O)(C₁₋₄ alkyl);—C(═O)OH; —CON(R′)(R″); —S(O)₁₋₂(NR′R″); —S(O)₁₋₂(C-4 alkyl); and cyano;each occurrence of R^(f) is independently selected from: H; C₁₋₄ alkyl;C₃₋₆ cycloalkyl; phenyl; —C(O)(C₁₋₄ alkyl); —C(O)O(C₁₋₄ alkyl);—CON(R′)(R″); —S(O)₁₋₂(NR′R″); —S(O)₁₋₂R^(h); —OH; and C₁₋₄ alkoxy;wherein each C₁₋₄ alkyl is optionally substituted with from 1-2independently selected R^(e); each C₃₋₆ cycloalkyl is optionallysubstituted with from 1-2 independently selected R^(g); and each phenylis optionally substituted with from 1-2 independently selected R^(d).each occurrence of R^(g) is independently selected from: C₁₋₆ alkyloptionally substituted with from 1-2 independently selected R^(e); C₁₋₄haloalkyl; —OH; oxo; F; Cl; Br; —NR^(j)R^(k); —N(R^(n))(C(═O)C₁₋₄alkyl); C₁₋₄ alkoxy; C₁₋₄ haloalkoxy; —C(═O)(C₁₋₄ alkyl); —C(═O)O(C₁₋₄alkyl); —C(═O)OH; —C(═O)N(R′)(R″); —S(O)₁₋₂(NR′R″); —S(O)₁₋₂(C₁₋₄alkyl); cyano; C₃₋₆ cycloalkyl optionally substituted with from 1-4independently selected C₁₋₄ alkyl; heteroaryl including from 5-10 ringatoms, wherein from 1-4 ring atoms are each independently selected fromN, N(R^(f)), O, and S, wherein the heteroaryl is optionally substitutedwith from 1-3 R^(m); and phenyl optionally substituted with from 1-4R^(m);each occurrence of R^(h) is independently selected from: C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, phenyl optionallysubstituted with from 1-3 R^(m), and heteroaryl including from 5-6 ringatoms, wherein from 1-4 ring atoms are each independently selected fromN, N(R^(f)), O, and S, wherein the heteroaryl is optionally substitutedwith from 1-3 R^(m);each occurrence of R^(j) and R^(k) is independently selected from: H andC₁₋₄ alkyl, which is optionally substituted with from 1-2 independentlyselected R^(u), wherein each occurrence of R^(u) is independentlyselected from: —OH, —N(R^(p))(R^(q)), —N(R^(n))(C(═O)C₁₋₄ alkyl),—N(R^(n))(C(═O)OC₁₋₄ alkyl), C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, —C(═O)(C₁₋₄alkyl); —C(═O)O(C₁₋₄ alkyl); —C(═O)OH; —C(═O)N(R^(p))(R^(q)),—S(O)₁₋₂(C₁₋₄ alkyl); —S(O)₁₋₂(N(R^(p))(R^(q))), and cyano;each occurrence of R^(m) is independently selected from: C₁₋₄ alkyl;C₁₋₄ haloalkyl; —OH, F, Cl, Br, —N(R^(j))(R^(k)), —N(R^(n))(C(═O)C₁₋₄alkyl), —N(R^(n))(C(═O)OC₁₋₄ alkyl), C₁₋₄ alkoxy, C₁₋₄ haloalkoxy,—C(═O)(C₁₋₄ alkyl); —C(═O)O(C₁₋₄ alkyl); —C(═O)OH,—C(═O)N(R^(p))(R^(q)), —S(O)₁₋₂(C₁₋₄ alkyl); —S(O)₁₋₂(N(R^(p))(R^(q))),and cyano;each occurrence of R^(n), R^(p), and R^(q) is independently selectedfrom: H and C₁₋₄ alkyl;each occurrence of R′ and R″ is independently selected from: H and C₁₋₄alkyl, which is optionally substituted with from 1-2 independentlyselected R^(u); or R′ and R″ together with the nitrogen atom to whicheach is attached forms a ring including from 3-8 ring atoms, wherein thering includes: (a) from 1-7 ring carbon atoms, each of which issubstituted with from 1-2 substituents independently selected from H andR^(s); and (b) from 0-3 ring heteroatoms (in addition to the nitrogenatom attached to R′ and R″), which are each independently selected fromN(R^(t)), O, and S;each occurrence of R^(s) is independently selected from: C₁₋₆ alkyloptionally substituted with from 1-2 independently selected R^(u); C₁₋₄haloalkyl; —OH; oxo; F; Cl; Br; —NR^(j)R^(k); —N(R^(n))(C(═O)C₁₋₄alkyl); C₁₋₄ alkoxy; C₁₋₄ haloalkoxy; —C(═O)(C₁₋₄ alkyl); —C(═O)O(C₁₋₄alkyl); —C(═O)OH; —C(═O)N(R^(p))(R^(q)); —S(O)₁₋₂(N(R^(p))(R^(q)));—S(O)₁₋₂(C₁₋₄ alkyl); cyano; heteroaryl including from 5-10 ring atoms,wherein from 1-4 ring atoms are each independently selected from N,N(R^(f)), O, and S, wherein the heteroaryl is optionally substitutedwith from 1-3 R^(m); phenyl optionally substituted with from 1-4 R^(m);and C₃₋₆ cycloalkyl optionally substituted with from 1-4 independentlyselected R^(u); andeach occurrence of R^(t) is independently selected from: H; C₁₋₄ alkyl;C₃₋₆ cycloalkyl; phenyl; —C(O)(C₁₋₄ alkyl); —C(O)O(C₁₋₄ alkyl);—CON(R^(p))(R^(q)); —S(O)₁₋₂(N(R^(p))(R^(q))), —S(O)₁₋₂R^(h); —OH; andC₁₋₄ alkoxy; wherein each C₁₋₄ alkyl is optionally substituted with from1-2 independently selected R^(u); each C₃₋₆ cycloalkyl is optionallysubstituted with from 1-4 independently selected R^(s); and each phenylis optionally substituted with from 1-2 independently selected R^(m).

In another aspect, compounds of Formula (I), or a pharmaceuticallyacceptable salt thereof, wherein:

W′ is R² or Q′-R²;

Q′ is NH, O, or S;

W is H, R², or Q-R²;Q is NR¹, CHR¹, O, or S;R¹ is independently H or C₁₋₄ alkyl;R² is independently R⁶ or -Q²-Y—R⁶;Q² is a bond or C(O);Y is independently C₁₋₁₀ alkylene which is optionally substituted withfrom 1-4 R^(e) and/or is optionally interrupted by one or more of thefollowing:

-   -   (i) O;    -   (ii) N(R^(f));    -   (iii) C₃₋₆ cycloalkylene optionally substituted with from 1 to 2        R^(g), (iv) C₆₋₁₀ arylene, optionally further substituted with        from 1 to 2 R^(d), (v) heteroarylene including from 5 to 6 ring        atoms, wherein from 1 to 4 ring atoms are each independently        selected from N, N(R^(f)), O, and S, and which is optionally        substituted with from 1 to 2 R^(g), or    -   (vi) heterocycloalkylene including from 5 to 6 ring atoms,        wherein from 1 to 2 ring atoms are each independently selected        from N, N(R^(f)), O and S(O)₁₋₂, and which is optionally further        substituted with from 1 to 2 R^(g),        R⁶ is independently selected from: H, —OH, C₁₋₄ alkoxy, C₁₋₄        haloalkoxy, —C(O)R^(a), —CO₂R^(a), —CONR′R″, —NR^(b)R^(c),        cyano; phenyl that is optionally substituted with from 1-3        independently selected R^(d); and heteroaryl including from 5 to        10 ring atoms, wherein from 1 to 4 ring atoms are each        independently selected from N, N(R^(f)), O, and S, wherein the        heteroaryl is optionally substituted with from 1-3 R^(d);        R³ is independently —(C₀₋₃ alkylene)-heteroaryl including 5 ring        atoms, wherein from 1 to 4 ring atoms are each independently        selected from N, NH, N(C₁₋₄ alkyl), O, and S, wherein the        heteroaryl is optionally substituted with from 1-3 R^(d);        R⁴ is independently selected from: hydrogen; halo; cyano; OH,        —CO₂H; —CO₂R^(a); —CONR′R″; C₁₋₄ haloalkyl; C₁₋₄ alkoxy; C₁₋₄        haloalkoxy; NR^(b)R^(c); and C₁₋₄ alkyl optionally substituted        with from 1-2 independently selected R^(e);

R^(a) is:

-   -   (i) C₁₋₈ alkyl optionally substituted with from 1-2        independently selected R^(e);    -   (ii) —(C₀₋₃ alkylene)-C₃₋₁₀ cycloalkyl, wherein the cycloalkyl        is optionally substituted with from 1-4 independently selected        R^(g);    -   (iii) —(C₀₋₃ alkylene)-heterocyclyl including from 3-10 ring        atoms, wherein from 1-3 ring atoms are each independently        selected from N(R^(f)), O, and S, wherein the heterocyclyl is        optionally substituted with from 1-4 independently selected        R^(g);    -   (iv) —(C₀₋₃ alkylene)-(C₆₋₁₀ aryl), wherein the aryl is        optionally substituted with from 1-5 independently selected        R^(d); or    -   (v) —(C₀₋₃ alkylene)-heteroaryl including from 5-10 ring atoms,        wherein from 1-4 ring atoms are each independently selected from        N, N(R^(f)), O, and S, wherein the heteroaryl is optionally        substituted with from 1-3 independently selected R^(d);        each occurrence of R^(b) and R^(c) is independently selected        from: H; R^(a); —C(O)(R^(a)), —C(O)O(R^(a)), —S(O)₁₋₂(R^(h)),        —C(O)NR′R″, —S(O)₁₋₂(NR′R″), —OH, and C₁₋₄ alkoxy;        each occurrence of R^(d) is independently selected from:        (i) halo;        (ii) cyano;        (iii) C₁₋₆ alkyl optionally substituted with from 1-2        independently selected R^(e);        (iv) C₂₋₆ alkenyl;        (v) C₂₋₆ alkynyl;        (vi) C₁₋₄ haloalkyl;        (vii) C₁₋₄ alkoxy;        (viii) C₁₋₄ haloalkoxy;        (ix) —(C₀₋₃ alkylene)-C₃₋₆ cycloalkyl optionally substituted        with from 1-4 independently selected C₁₋₄ alkyl;        (x) —(C₀₋₃ alkylene)-heterocyclyl including from 3-10 ring        atoms, wherein from 1-3 ring atoms are each independently        selected from N(R^(f)), O, and S, wherein the heterocyclyl is        optionally substituted with from 1-4 independently selected C₁₋₄        alkyl;        (xi) —(C₀₋₃ alkylene)-phenyl optionally substituted with from        1-3 R^(m);        (xii) —(C₀₋₃ alkylene)-heteroaryl including from 5-10 ring        atoms, wherein from 1-4 ring atoms are each independently        selected from N, N(R^(f)), O, and S, wherein the heteroaryl is        optionally substituted with from 1-3 R^(m);        (xiii) —NR^(j)R^(k);

(xv) —OH;

(xvii) —C(═O)(C₁₋₄ alkyl);(xviii) —C(═O)O(C₁₋₄ alkyl);(xix) —C(═O)OH, and

(xx) —C(═O)N(R′)(R″);

each occurrence of R^(e) is independently selected from: —OH; F; C₁₋₄alkoxy; C₁₋₄ haloalkoxy; and cyano;each occurrence of R^(f) is independently selected from: H; C₁₋₄ alkyl;C₃₋₆ cycloalkyl; phenyl; and —C(O)(C₁₋₄ alkyl);each occurrence of R^(g) is independently selected from: C₁₋₆ alkyloptionally substituted with from 1-2 independently selected R^(e); C₁₋₄haloalkyl; —OH; oxo; F; Cl; Br; —NR^(j)R^(k); C₁₋₄ alkoxy; C₁₋₄haloalkoxy; —C(═O)(C₁₋₄ alkyl); —C(═O)O(C₁₋₄ alkyl); —C(═O)OH;—C(═O)N(R′)(R″); —S(O)₁₋₂(NR′R″); —S(O)₁₋₂(C₁₋₄ alkyl); cyano; C₃₋₆cycloalkyl optionally substituted with from 1-4 independently selectedC₁₋₄ alkyl; heteroaryl including from 5-10 ring atoms, wherein from 1-4ring atoms are each independently selected from N, N(R^(f)), O, and S,wherein the heteroaryl is optionally substituted with from 1-3 R^(m);and phenyl optionally substituted with from 1-4 R^(m);each occurrence of R^(j) and R^(k) is independently H or C₁₋₄ alkyl;each occurrence of R^(m) is independently selected from: C₁₋₄ alkyl;C₁₋₄ haloalkyl; —OH, F, Cl, Br, —N(R^(j))(R^(k)), C₁₋₄ alkoxy, C₁₋₄haloalkoxy, and cyano;each occurrence of R′ and R″ is independently selected from: H and C₁₋₄alkyl; or R′ and R″ together with the nitrogen atom to which each isattached forms a ring including from 3-8 ring atoms, wherein the ringincludes: (a) from 1-7 ring carbon atoms, each of which is substitutedwith from 1-2 substituents independently selected from H and R^(s); and(b) from 0-3 ring heteroatoms (in addition to the nitrogen atom attachedto R′ and R″), which are each independently selected from NH, N(C₁₋₄alkyl), O, and S; andR^(s) is independently selected from: C₁₋₆ alkyl; C₁₋₄ haloalkyl; —OH;oxo; F; Cl; Br; —NR^(j)R^(k); C₁₋₄ alkoxy; C₁₋₄ haloalkoxy; and cyano.

In another aspect, compounds of Formula (I), or a pharmaceuticallyacceptable salt thereof, wherein:

W′ is independently R⁶ or -Q²-Y—R⁶;W is independently H, R⁶, -Q²-Y—R⁶, or -Q-Q²-Y—R⁶;Q is independently selected from NH, N(C₁₋₄ alkyl), O, and CH₂;Q² is independently a bond or C(O);Y is independently C₁₋₈ alkylene, which is optionally substituted withfrom 1-2 R^(e) and/or is optionally interrupted by one or more of thefollowing:

-   -   (i) O;    -   (ii) N(R^(f));    -   (iii) C₃₋₆ cycloalkylene optionally substituted with from 1 to 2        R^(g);    -   (iv) phenylene optionally further substituted with from 1 to 2        R^(d);    -   (v) heteroarylene including from 5 to 6 ring atoms, wherein from        1 to 4 ring atoms are each independently selected from N,        N(R^(f)), O, and S, and the heteroarylene is optionally        substituted with from 1 to 2 R^(g); or    -   (vi) heterocycloalkylene including from 3 to 7 ring atoms,        wherein from 1 to 2 ring atoms are each independently selected        from N, N(R^(f)), O and S(O)₁₋₂, and the heterocycloalkylene is        optionally further substituted with from 1 to 2 R^(g);        R³ is independently heteroaryl including 5 ring atoms, wherein        from 1 to 4 ring atoms are each independently selected from N,        NH, N(C₁₋₄ alkyl), O, and S, wherein the heteroaryl is        optionally substituted with from 1-3 R^(d);        R⁴ is independently selected from: H, halo, C₁₋₄ alkyl, C₁₋₄        haloalkyl; C₁₋₄ alkoxy; and C₁₋₄ haloalkoxy;        R⁶ is independently selected from: H, OH, CN, C₁₋₄ alkoxy, OBn,        —NR^(b)R^(c), —NR^(b)COR^(a), —NHC(O)O(C₁₋₄ alkyl), —CONR′R″,        —NR^(b)C(O)NH(C₁₋₄ alkyl), —NR^(b)C(O)N(C₁₋₄ alkyl)₂,        —NHS(O)₂(C₁₋₄ alkyl), —S(O)₂(C₁₋₄ alkyl); heterocyclyl including        from 3-10 ring atoms, wherein from 1-3 ring atoms are each        independently selected from N, N(R^(f)) and O, wherein the        heterocyclyl is optionally substituted with from 1-4 R^(g);        phenyl optionally substituted with from 1-3 R^(d); and        heteroaryl including from 5 to 10 ring atoms, wherein from 1 to        4 ring atoms are each independently selected from N, N(R^(f)),        O, and S, wherein the heteroaryl is optionally substituted with        from 1-3 R^(d);        R^(a) is independently selected from: C₁₋₄ alkyl, phenyl        substituted with 0 to 2 R^(d), and heteroaryl including from 5        to 6 ring atoms, wherein from 1 to 4 ring atoms are each        independently selected from N, N(R^(f)), O, and S, wherein the        heteroaryl is substituted 0 to 2 R^(d);        R^(b) is independently H or C₁₋₄ alkyl;        R^(c) is independently H or C₁₋₄ alkyl;        R^(d) is independently halo, C₁₋₄ alkoxy, —C(O)O(C₁₋₄ alkyl), or        C₁₋₄ alkyl substituted with from 0 to 2 R^(e);        R^(e) is independently F or OH;        R^(f) is independently H, C₁₋₄ alkyl, —C(O)O(C₁₋₄ alkyl), or        —C(O)O(C₁₋₄ alkyl);        R^(g) is independently selected from: C₁₋₄ alkyl, C₁₋₄        haloalkyl, —OH, oxo, F, Cl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, and        N(C₁₋₄ alkyl)₂;        each occurrence of R′ and R″ is independently selected from: H        and C₁₋₄ alkyl; or R′ and R″ together with the nitrogen atom to        which each is attached forms a ring including from 5 to 6 ring        atoms, wherein the ring includes: (a) from 3 to 5 ring carbon        atoms, each of which is substituted with from 1 to 2        substituents independently selected from H and R^(s); and (b)        from 0 to 2 ring heteroatoms (in addition to the nitrogen atom        attached to R′ and R″), which are each independently selected        from NH, N(C₁₋₄ alkyl), O, and S; and        R^(s) is independently selected from: C₁₋₄ alkyl, C₁₋₄        haloalkyl, —OH; oxo, F, Cl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, and        cyano.

In another aspect, compounds of Formula (I), or a pharmaceuticallyacceptable salt thereof, wherein:

W′ is independently R⁶ or -Q²-Y—R⁶;W is independently H or -Q-Q²-Y—R;Q is independently selected from NH, N(C₁₋₄ alkyl), O, and CH₂;Q² is independently a bond or C(O);Y is independently C₁₋₈ alkylene, which is optionally substituted withfrom 1-2 R^(e) and/or is optionally interrupted by one or more of thefollowing:

-   -   (i) O;    -   (ii) N(R^(f));    -   (iii) C₃₋₆ cycloalkylene optionally substituted with from 1 to 2        R^(g);    -   (iv) phenylene optionally further substituted with from 1 to 2        R^(d);    -   (v) heteroarylene including from 5 to 6 ring atoms, wherein from        1 to 4 ring atoms are each independently selected from N,        N(R^(f)), O, and S, and the heteroarylene is optionally        substituted with from 1 to 2 R^(g); or    -   (vi) heterocycloalkylene including from 5 to 6 ring atoms,        wherein from 1 to 2 ring atoms are each independently selected        from N, N(R^(f)), O and S(O)₁₋₂, and the heterocycloalkylene is        optionally further substituted with from 1 to 2 R^(g);        R³ is independently heteroaryl including 5 ring atoms, wherein        from 1 to 4 ring atoms are each independently selected from N,        NH, N(C₁₋₄ alkyl), O, and S, wherein the heteroaryl is        optionally substituted with from 1-3 R^(d);        R⁴ is independently selected from: H, halo, C₁₋₄ alkyl, C₁₋₄        haloalkyl; C₁₋₄ alkoxy; and C₁₋₄ haloalkoxy;        R⁶ is independently selected from: H, OH, C₁₋₄ alkoxy, OBn,        —NR^(b)R^(c), —NR^(b)COR^(a), —NHC(O)O(C₁₋₄ alkyl), —CONR′R″,        —NR^(b)C(O)NH(C₁₋₄ alkyl), —NR^(b)C(O)N(C₁₋₄ alkyl)₂,        —NHS(O)₂(C₁₋₄ alkyl), —S(O)₂(C₁₋₄ alkyl), and heteroaryl        including from 5 to 10 ring atoms, wherein from 1 to 4 ring        atoms are each independently selected from N, N(R^(f)), O, and        S, wherein the heteroaryl is optionally substituted with from        1-3 R^(d);        R^(a) is independently selected from: C₁₋₄ alkyl, phenyl        substituted with 0 to 2 R^(d), and heteroaryl including from 5        to 6 ring atoms, wherein from 1 to 4 ring atoms are each        independently selected from N, N(R^(f)), O, and S, wherein the        heteroaryl is substituted 0 to 2 R^(d);        R^(b) is independently H or C₁₋₄ alkyl;        R^(c) is independently H or C₁₋₄ alkyl;        R^(d) is independently C₁₋₄ alkoxy or C₁₋₄ alkyl substituted        with from 0 to 2 R^(e);        R^(e) is independently F or OH;        R^(f) is independently H or C₁₋₄ alkyl;        R^(g) is independently selected from: C₁₋₄ alkyl, C₁₋₄        haloalkyl, —OH, oxo, F, Cl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, and        N(C₁₋₄ alkyl)₂;        each occurrence of R′ and R″ is independently selected from: H        and C₁₋₄ alkyl; or R′ and R″ together with the nitrogen atom to        which each is attached forms a ring including from 5 to 6 ring        atoms, wherein the ring includes: (a) from 3 to 5 ring carbon        atoms, each of which is substituted with from 1 to 2        substituents independently selected from H and R^(s); and (b)        from 0 to 2 ring heteroatoms (in addition to the nitrogen atom        attached to R′ and R″), which are each independently selected        from NH, N(C₁₋₄ alkyl), O, and S; and        R^(s) is independently selected from: C₁₋₄ alkyl, C₁₋₄        haloalkyl, —OH; oxo, F, Cl, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, and        cyano.

In some embodiments, it is provided that at least one of W′ and W is asubstituent other than H.

In another aspect, compounds of Formula (I), or a pharmaceuticallyacceptable salt thereof, wherein:

W′ is H;

W is independently -Q-Y—R⁶,

or heteroaryl including from 5 to 6 ring atoms, wherein from 1 to 4 ringatoms are each independently selected from N, NH, N(R^(f)), O, and S,wherein the heteroaryl is optionally substituted with from 1-2 R^(d);

Q is independently selected from NH, N(C₁₋₄ alkyl), O, and CH₂;

Y is C₁₋₆ alkylene, which is optionally substituted with from 1-2 R^(e)and/or is optionally interrupted by one or more of the following:

-   -   (i) O;    -   (ii) N(R^(f));    -   (iii) C₃₋₆ cycloalkylene optionally substituted with from 1 to 2        R^(g); or    -   (iv) heterocycloalkylene including from 5 to 6 ring atoms,        wherein from 1 to 2 ring atoms are each independently selected        from N, N(R^(f)), O and S(O)₁₋₂, and the heterocycloalkylene is        optionally further substituted with from 1 to 2 R^(g),

R³ is independently pyrazolyl, thienyl or isothiazolyl;

R⁴ is independently H or F;

R⁶ is independently selected from: H, OH, CN, C₁₋₄ alkoxy, phenyl,—NR^(b)R^(c), —NR^(b)COR^(a), —NHC(O)O(C₁₋₄ alkyl), —C(O)NH(C₁₋₄ alkyl),—C(O)N(C₁₋₄ alkyl)₂, —NR^(b)C(O)NH(C₁₋₄ alkyl), —NR^(b)C(O)N(C₁₋₄alkyl)₂, —S(O)₂(C₁₋₄ alkyl), —NHS(O)₂(C₁₋₄ alkyl),

—CO-morpholinyl, phenyl, and heteroaryl including from 5 to 6 ringatoms, wherein from 1 to 3 ring atoms are each independently selectedfrom N, N(R^(f)), O, and S, wherein said phenyl and heteroaryl areoptionally substituted with from 1-2 R^(d);

R^(a) is independently selected from: C₁₋₄ alkyl, phenyl, and heteroarylincluding from 5 to 6 ring atoms, wherein from 1 to 4 ring atoms areeach independently selected from N, N(R^(f)), O, and S; wherein thephenyl and heteroaryl are substituted with 0 to 2 R^(d);

R^(b) is independently H or C₁₋₄ alkyl;

R^(c) is independently H or C₁₋₄ alkyl;

R^(d) is independently F, C₁₋₄ alkyl, C₁₋₄ alkoxy, or —NHSO₂(C₁₋₄alkyl);

R^(e) is independently F or OH;

R^(f) is independently H, C₁₋₄ alkyl, —C(O)(C₁₋₄ alkyl) or —C(O)O(C₁₋₄alkyl); and

R^(g) is independently selected from: F, Cl, C₁₋₄ alkyl, —OH, and oxo.

In another aspect, compounds of Formula (I), or a pharmaceuticallyacceptable salt thereof, wherein:

W′ is H;

W is independently -Q-Y—R⁶,

or heteroaryl including from 5 to 6 ring atoms, wherein from 1 to 4 ringatoms are each independently selected from N, NH, N(C₁₋₄ alkyl), O, andS, wherein the heteroaryl is optionally substituted with from 1-2 R^(d);

Q is independently selected from NH, N(C₁₋₄ alkyl), O, and CH₂;

Y is C₁₋₆ alkylene, which is optionally substituted with from 1-2 R^(e)and/or is optionally interrupted by one or more of the following:

-   -   (i) O;    -   (ii) N(R^(f));    -   (iii) C₃₋₆ cycloalkylene optionally substituted with from 1 to 2        R^(g); or    -   (iv) heterocycloalkylene including from 5 to 6 ring atoms,        wherein from 1 to 2 ring atoms are each independently selected        from N, N(R^(f)), O and S(O)₁₋₂, and the heterocycloalkylene is        optionally further substituted with from 1 to 2 R^(g),

R³ is independently pyrazolyl or isothiazolyl;

R⁴ is H;

R⁶ is independently selected from: H, OH, C₁₋₄ alkoxy, phenyl,—NR^(b)R^(c), —NR^(b)COR^(a), —NHC(O)O(C₁₋₄ alkyl), —C(O)NH(C₁₋₄ alkyl),—C(O)N(C₁₋₄ alkyl)₂, —NR^(b)C(O)NH(C₁₋₄ alkyl), —NR^(b)C(O)N(C₁₋₄alkyl)₂, —NHS(O)₂(C₁₋₄ alkyl), —S(O)₂(C₁₋₄ alkyl),

and heteroaryl including from 5 to 6 ring atoms, wherein from 1 to 3ring atoms are each independently selected from N, N(R^(f)), O, and S,wherein the heteroaryl is optionally substituted with from 1-2 R^(d);

R^(a) is independently selected from: C₁₋₄ alkyl, phenyl, heteroarylincluding from 5 to 6 ring atoms, wherein from 1 to 4 ring atoms areeach independently selected from N, N(R^(f)), O, and S; wherein thephenyl and heteroaryl are substituted with 0 to 2 R^(d);

R^(b) is independently H or C₁₋₄ alkyl;

R^(c) is independently H or C₁₋₄ alkyl;

R^(d) is independently C₁₋₄ alkyl or C₁₋₄ alkoxy;

R^(e) is independently F or OH;

R^(f) is independently H or C₁₋₄ alkyl; and

R^(g) is independently selected from: F, Cl, C₁₋₄ alkyl, —OH, and oxo.

In another aspect, compounds of Formula (I), or a pharmaceuticallyacceptable salt thereof, wherein:

W′ is H;

W is independently selected from: -Q-Y—R⁶, pyrazolyl, NR^(f)-pyrazolyl,imidazolyl, N(C₁₋₄ alkyl)₂, —O(CH₂)₂₋₃CH₃, —(CH₂)₃-OBn,

Q is independently selected from NH, N(C₁₋₄ alkyl), O, and CH₂;

Y is C₁₋₆ alkylene, which is optionally substituted with from 1-2 R^(e)and/or is optionally interrupted by O;

R³ is independently pyrazolyl or thienyl;

R⁴ is independently H or F;

R⁶ is independently selected from: H, OH, CN, C₁₋₄ alkoxy, —NR^(b)R^(c),—NR^(b)COR^(a), —NHC(O)O(C₁₋₄ alkyl), —C(O)NH(C₁₋₄ alkyl), —C(O)N(C₁₋₄alkyl)₂, —NR^(b)C(O)NH(C₁₋₄ alkyl), —NR^(b)C(O)N(C₁₋₄ alkyl)₂,—S(O)₂(C₁₋₄ alkyl), —NHS(O)₂(C₁₋₄ alkyl),

morpholinyl, —CO-morpholinyl, phenyl and heteroaryl selected fromthienyl, oxazolyl, thiazolyl, imidazolyl, N(C₁₋₄ alkyl)-imidazolyl,pyrazolyl, N(C₁₋₄ alkyl)-pyrazolyl, trizolyl, N(C₁₋₄ alkyl)-trizolyl,pyridyl, pyrimidinyl, and pyridazinyl, wherein said phenyl andheteroaryl are substituted with 0 to 2 R^(d);

R^(a) is independently C₁₋₄ alkyl, phenyl or heteroaryl selected fromthiazolyl, N—(C₁₋₄ alkyl)-imidazolyl, and pyridyl; wherein the phenyland heteroaryl are substituted with 0 to 2 R^(d);

R^(b) is independently H or C₁₋₄ alkyl;

R^(c) is independently H or C₁₋₄ alkyl;

R^(d) is independently selected from F, C₁₋₄ alkyl, C₁₋₄ alkoxy, and—NHSO₂(C₁₋₄ alkyl);

R^(e) is independently F or OH; and

R^(f) is independently H, CH₂CH₂OH, or —C(O)O(C₁₋₄ alkyl).

In another aspect, compounds of Formula (I), or a pharmaceuticallyacceptable salt thereof, wherein:

W′ is H;

W is independently selected from: -Q-Y—R⁶, imidazolyl, N(C₁₋₄ alkyl)₂,—O(CH₂)₂₋₃CH₃, —(CH₂)₃-OBn,

Q is independently selected from NH, N(C₁₋₄ alkyl), O, and CH₂;

Y is C₁₋₆ alkylene, which is optionally substituted with from 1-2 R^(e)and/or is optionally interrupted by O;

R³ is independently pyrazolyl;

R⁴ is H;

R⁶ is independently selected from: OH, C₁₋₄ alkoxy, —NR^(b)R^(c),—NR^(b)COR^(a), —NHC(O)O(C₁₋₄ alkyl), —C(O)NH(C₁₋₄ alkyl), —C(O)N(C₁₋₄alkyl)₂, —NR^(b)C(O)NH(C₁₋₄ alkyl), —NR^(b)C(O)N(C₁₋₄ alkyl)₂,—NHS(O)₂(C₁₋₄ alkyl), —S(O)₂(C₁₋₄ alkyl),

and heteroaryl selected from thiazolyl, imidazolyl, pyrazolyl, trizolyl,pyridyl, pyridazinyl, wherein the heteroaryl is substituted with 0 to 2R^(d);

R^(a) is independently selected from: C₁₋₄ alkyl, phenyl, heteroarylselected from thiazolyl, N—(C₁₋₄ alkyl)-imidazolyl, and pyridyl; whereinthe phenyl and heteroaryl are substituted with 0 to 2 R^(d);

R^(b) is independently H or C₁₋₄ alkyl;

R^(c) is independently H or C₁₋₄ alkyl;

R^(d) is C₁₋₄ alkyl; and

R^(e) is independently F or OH.

In another aspect, compounds of Formula (I), or a pharmaceuticallyacceptable salt thereof, wherein:

W′ is H;

W is independently selected from: pyrazolyl, —(CH₂)₁₋₅—R⁶,—O—(CH₂)₁₋₄—R⁶, —NH—(CH₂)₁₋₄—R⁶, —N(CH₃)—(CH₂)₁₋₄—R⁶, —(CH₂)₃-OBn,—O—CH(CH₂OH)₂, —O—CH₂CH(OH)(CH₂OH), —O—(CH₂)₁₋₂—C(CH₃)₂OH,—O—(CH₂)₁₋₂—C(CH₃)₂CH₂OH, —O—CH₂C(CH₃)(CH₂OH)₂,—NH—(CH₂)₁₋₂—CH(OH)CH₂OH, —NH—CH(CH₃)CH₂OH, —NH—(CH₂)₁₋₂—CH(CH₃)OH,—NH—(CH₂)₁₋₂—C(CH₃)₂OH, —NH—(CH₂)₁₋₂—C(CH₃)₂CH₂OH, —NH—CH(CH₂OH)₂,—NH—(CH₂)₁₋₂—CH(OH)CH₂OH, —NH—(CH₂)₁₋₂—CH(OH)CH₂OCH₃,—NH—(CH₂)₁₋₂—C(CH₃)₂SO₂(CH₃), —NH—(CH₂)₁₋₂—CF₂(pyridyl),—NH—(CH₂)₁₋₂—CH(OH)(pyridyl),

R³ is independently

R⁴ is independently H or F;

R⁶ is independently selected from: H, OH, CN, C₁₋₄ alkoxy, —NR^(b)R^(c),—NR^(b)COR^(a), —NHC(O)O(C₁₋₄ alkyl), —C(O)NH(C₁₋₄ alkyl), —C(O)N(C₁₋₄alkyl)₂, —NR^(b)C(O)N(C₁₋₄ alkyl)₂, —S(O)₂(C₁₋₄ alkyl), —NHS(O)₂(C₁₋₄alkyl), phenyl, and heteroaryl selected from thienyl, oxazolyl,pyrazolyl, N(C₁₋₄ alkyl)-pyrazolyl, thiazolyl, imidazolyl, N(C₁₋₄alkyl)-imidazolyl, trizolyl, N(C₁₋₄ alkyl)-trizolyl, pyridyl,pyrimidinyl, and pyridazinyl, wherein said phenyl and heteroaryl aresubstituted with 0 to 2 R^(d);

R^(a) is independently C₁₋₄ alkyl, phenyl or heteroaryl selected fromthiazolyl, N—(C₁₋₄ alkyl)-imidazolyl, and pyridyl; wherein theheteroaryl is substituted with 0 to 2 R^(d);

R^(b) is independently H or C₁₋₄ alkyl;

R^(c) is independently H or C₁₋₄ alkyl; and

R^(d) is independently selected from F, C₁₋₄ alkyl, C₁₋₄ alkoxy, and—NHSO₂(C₁₋₄ alkyl).

In another aspect, compounds of Formula (I), or a pharmaceuticallyacceptable salt thereof, wherein:

W′ is H;

W is independently selected from: —(CH₂)₁₋₅—R⁶, —O—(CH₂)₂₋₄—R⁶,—NH—(CH₂)₁₋₄—R⁶, —(CH₂)₃-OBn, —O—CH(CH₂OH)₂, —NH—(CH₂)₁₋₂—C(OH)CH₂OH,—NH—C(CH₃)CH₂OH, —O—(CH₂)₁₋₂—C(CH₃)₂OH, —NH—(CH₂)₁₋₂—CH(CH₃)OH,—NH—(CH₂)₁₋₂—C(CH₃)₂OH, —NH—(CH₂)₁₋₂—CF₂(pyridyl),—NH—(CH₂)₁₋₂—CH(OH(pyridyl),

R³ is independently 1H-pyrazol-3-yl or pyrazol-1-yl;

R⁴ is H;

R⁶ is independently selected from: OH, C₁₋₄ alkoxy, —NR^(b)R^(c),—NR^(b)COR^(a), —NHC(O)O(C₁₋₄ alkyl), —C(O)NH(C₁₋₄ alkyl), —C(O)N(C₁₋₄alkyl)₂, —NR^(b)C(O)N(C₁₋₄ alkyl)₂, —NHS(O)₂(C₁₋₄ alkyl), —S(O)₂(C₁₋₄alkyl), and heteroaryl selected from pyrazolyl, thiazolyl, imidazolyl,trizolyl, pyridyl, and pyridazinyl, wherein the heteroaryl issubstituted with 0 to 2 R^(d);

R^(a) is independently C₁₋₄ alkyl or heteroaryl selected from thiazolyl,N—(C₁₋₄ alkyl)-imidazolyl, and pyridyl; wherein the heteroaryl issubstituted with 0 to 2 R^(d);

R^(b) is independently H or C₁₋₄ alkyl;

R^(c) is independently H or C₁₋₄ alkyl; and

R^(d) is independently C₁₋₄ alkyl.

In another aspect, compounds of Formula (I), or a pharmaceuticallyacceptable salt thereof, wherein:

W′ is H;

W is independently selected from: pyrazolyl, —(CH₂)₁₋₄—R⁶,—O—(CH₂)₁₋₄—R⁶, —NH—(CH₂)₁₋₄—R⁶, —(CH₂)₃-OBn, —O—CH(CH₂OH)₂,—O—CH₂CH(OH)(CH₂OH), —O—(CH₂)₁₋₂—C(CH₃)₂CH₂OH, —NH—(CH₂)₁₋₂—CH(CH₃)OH,—NH—CH(CH₃)CH₂OH, —NH—(CH₂)₁₋₂—C(CH₃)₂OH, —NH—(CH₂)₁₋₂—C(CH₃)₂CH₂OH,—NH—CH(CH₂OH)₂, —NH—(CH₂)₁₋₂—CH(OH)CH₂OH, —NH—(CH₂)₁₋₂—CH(OH)CH₂OCH₃,—NH—(CH₂)₁₋₂—C(CH₃)₂SO₂(CH₃), —NH—(CH₂)₁₋₂—CF₂(pyrid-1-yl),—NH—(CH₂)₁₋₂—CH(OH)(pyridyl),

R³ is independently

R⁴ is independently H or F;

R⁶ is independently selected from: H, OH, CN, C₁₋₄ alkoxy, —C(O)NHCH₃,—N(CH₂CH₃)C(O)CH₃, —NHC(O)(OCH₃), —NHC(O)NH₂CHCH₃, —NHC(O)N(CH₃)₂,—SO₂(CH₃), —NHS(O)₂CH₃, —NHCOR^(a), phenyl and heteroaryl selected fromthienyl, oxazolyl, pyrazolyl, N—CH₃-pyrazolyl, thiazolyl, imidazolyl,N—CH₃-imidazolyl, trizolyl, N—CH₃-trizolyl, pyridyl, pyrimidinyl, andpyridazinyl, wherein said phenyl and heteroaryl are substituted with 0to 2 R^(d);

R^(a) is independently selected from C₁₋₄ alkyl, 2-(CH₃)-thiazol-4-yland N—(CH₃)-imidazol-2-yl; and

R^(d) is independently selected from F, C₁₋₄ alkyl, C₁₋₄ alkoxy, and—NHSO₂(CH₃).

In another aspect, compounds of Formula (I), or a pharmaceuticallyacceptable salt thereof, wherein:

W′ is H;

W is independently selected from: —(CH₂)₁₋₄—R⁶, —O—(CH₂)₁₋₄—R⁶,—NH—(CH₂)₁₋₄—R⁶, —(CH₂)₃-OBn, —O—CH(CH₂OH)₂, —NH—(CH₂)₁₋₂—CH(CH₃)OH,—NH—(CH₂)₁₋₂—C(CH₃)₂OH, —NH—(CH₂)₁₋₂—CF₂(pyrid-1-yl), and

R³ is independently 1H-pyrazol-3-yl or pyrazol-1-yl;

R⁴ is H;

R⁶ is independently selected from: OH, —N(CH₂CH₃)C(O)CH₃,—NHC(O)N(CH₃)₂, —NHCOR^(a) and heteroaryl selected from pyrazolyl,thiazolyl, imidazolyl, trizolyl, pyridyl, and pyridazinyl, wherein theheteroaryl is substituted with 0 to 2 R^(d);

R^(a) is independently selected from C₁₋₄ alkyl, 2-(CH₃)-thiazol-4-yland N—(CH₃)-imidazol-2-yl; and

R^(d) is independently C₁₋₄ alkyl.

In another aspect, compounds of Formula (I), or a pharmaceuticallyacceptable salt thereof, wherein:

W′ is independently selected from: —Y—R⁶, —CONH(pyrid-3-yl),

and heteroaryl selected from imidazolyl, pyrazolyl, trizolyl, pyridyland indazolyl, wherein the heteroaryl is substituted with 0 to 2 R^(d);

Y is —(CH₂)₁₋₅— or —(CH₂)₃₋₅—O—(CH₂)₁₋₂;

W is H;

R³ is independently pyrazolyl;

R⁴ is H; and

R⁶ is independently selected from: OH, OBn, C₁₋₄ alkoxy, phenyl,—NH(C₁₋₄ alkyl), —NHC(O)(C₁₋₄ alkyl), —N(C₁₋₄ alkyl)C(O)(C₁₋₄ alkyl),

R^(d) is independently CH₂OH or C₁₋₄ alkyl.

In another aspect, compounds of Formula (I), or a pharmaceuticallyacceptable salt thereof, wherein:

W′ is independently selected from: —(CH₂)₃₋₅—OH, —(CH₂)₃₋₅-OBn,—(CH₂)₃₋₄—NHCH₂CH₃, —(CH₂)₃₋₄—NHC(O)CH₃, CH₂)₃₋₄—N(CH₂CH₃C(O)CH₃,6-(CH₂OH)-pyrid-2-yl, imidazolyl,

W is H;

R³ is 1H-pyrazol-3-yl; and

R⁴ is H.

In another aspect, compounds of Formula (I), or a pharmaceuticallyacceptable salt thereof, wherein:

W′ is independently selected from: —Y—R⁶, —CONH(pyrid-3-yl),

and heteroaryl selected from imidazolyl, pyridyl and indazolyl, whereinthe heteroaryl is substituted with 0 to 2 R^(d);

Y is —(CH₂)₁₋₅— or —(CH₂)₃₋₅—O—(CH₂)₁₋₂;

W is H;

R³ is independently pyrazolyl;

R⁴ is H; and

R⁶ is independently selected from: OH, C₁₋₄ alkoxy, phenyl, —NH(C₁₋₄alkyl), —N(C₁₋₄ alkyl)C(O(C₁₋₄ alkyl),

and

R^(d) is independently CH₂OH or C₁₋₄ alkyl.

In another aspect, compounds of Formula (I), or a pharmaceuticallyacceptable salt thereof, wherein:

W′ is independently selected from: —(CH₂)₃₋₅—OH, —(CH₂)₃₋₅-OBn,—(CH₂)₃₋₄—NHCH₂CH₃, —(CH₂)₃₋₄—N(CH₂CH₃)C(O)CH₃, —CONH(pyrid-3-yl),6-(CH₂OH)-pyrid-2-yl,

W is H;

R³ is 1H-pyrazol-3-yl; and

R⁴ is H.

In another aspect, compounds of Formula (I), or a pharmaceuticallyacceptable salt thereof, wherein: (generalized from a list of 19compounds)

W′ is H;

W is independently selected from: —O—CH₂CH(OH)(CH₂OH), —NH—(CH₂)₃₋₄—OH,—NH—(CH₂)₁₋₂—CH(CH₃)OH, —NH—(CH₂)₁₋₂—C(CH₃)₂OH, —O—(CH₂)₁₋₂-(pyrazolyl),—NH—(CH₂)₁₋₂-(pyrazolyl), —NH—(CH₂)₁₋₂-(pyrimidinyl),—NH—CH₂)₁₋₂-(pyridazinyl), —NH—(CH₂)₁₋₂—CF₂(pyridyl),

R³ is independently

and

R⁴ is independently H or F.

In another aspect, compounds of Formula (I), or a pharmaceuticallyacceptable salt thereof, wherein: (generalized from a list of 12compounds)

W′ is H;

W is independently selected from: —O—CH₂CH(OH)(CH₂OH), —NH—(CH₂)₃₋₄—OH,—NH—(CH₂)₁₋₂—CH(CH₃)OH, —NH—(CH₂)₁₋₂—C(CH₃)₂OH,—NH—(CH₂)₁₋₂-(pyrazolyl), and

R³ is independently

and

R⁴ is independently H or F.

In another aspect, compounds of Formula (I), or a pharmaceuticallyacceptable salt thereof, wherein: (generalized from a short list of 7compounds)

W′ is H;

W is independently selected from: —O—CH₂CH(OH)(CH₂OH), —NH—(CH₂)₃₋₄—OH,—NH—(CH₂)₁₋₂—CH(CH₃)OH, —NH—(CH₂)₁₋₂—C(CH₃)₂OH,—NH—(CH₂)₁₋₂-(pyrazolyl), and

R³ is

and

R⁴ is independently H or F.

In another aspect, a compound is selected from:

or a pharmaceutically acceptable salt thereof.

In another aspect, a compound is selected from:

or a pharmaceutically acceptable salt thereof.

In another aspect, a compound is selected from:

or a pharmaceutically acceptable salt thereof.

In another aspect, a compound is selected from:

or a pharmaceutically acceptable salt thereof.

Variables W, W′, O, and O′

In some embodiments, W′ is R².

In some embodiments, W′ is Q′-R².

In some embodiments, Q′ is NH.

In some embodiments, Q′ is O.

In some embodiments, Q′ is S.

In some embodiments, W is H.

In some embodiments, W is R².

In some embodiments, W is Q-R².

In some embodiments, Q is NR¹.

In some embodiments, Q is CHR¹.

In some embodiments, Q is O.

In some embodiments, Q is S.

In some embodiments, W′ is R² (e.g., Y—R⁶, e.g., hydroxyalkyl) and W isH.

In some embodiments, W′ is R² (e.g., H) and W is R² (e.g., Y—R⁶, e.g.,hydroxyalkyl).

In some embodiments, W′ is R²; W is Q-R²; and Q is CHR¹.

In some embodiments, W′ is R²; W is Q-R²; and Q is NR¹.

In some embodiments, W′ is R²; W is Q-R²; and Q is O.

In some embodiments, W′ is R²; W is Q-R²; and Q is S.

In some embodiments, W′ is R² and W is H.

In some embodiments, W is R² and W′ is H.

Variable R²

In some embodiments, R² is selected from: H, R⁶, and Q²-Y—R⁶. In certainembodiments, R² is selected from: R⁶ and Q²-Y—R⁶.

In certain embodiments, R² is H.

In certain embodiments, R² is Q²-Y—R⁶.

In certain of these embodiments, Q² is bond. In other embodiments, Q² isO or S (e.g., O).

In certain of these embodiments, Y is selected from: C₁₋₁₀ alkylene,C₂₋₁₀ alkenylene, and C₂₋₁₀ alkynylene, each of which is optionallysubstituted with from 1-4 R^(e). In certain of these embodiments, Y isselected from: C₁₋₁₀ alkylene, C₂₋₁₀ alkenylene, and C₂₋₁₀ alkynylene,each of which is unsubstituted. For example, Y can be unsubstitutedC₁₋₁₀ alkylene. As another example, Y can be C₁₋₁₀ alkylene, which issubstituted with from 1-4 R^(e). In certain of the foregoingembodiments, Y is unbranched. In other of the foregoing embodiments, Yis branched. In other of the foregoing embodiments, Y is interrupted byone or more (e.g., one) of the following:

-   -   (i) O;    -   (ii) S;    -   (iii) N(R^(f));    -   (iv) C₃₋₆ cycloalkylene optionally substituted with from 1-4        R^(g),    -   (v) C₆₋₁₀ arylene, optionally further substituted with from 1-4        R^(d),    -   (vi) heteroarylene including from 5-10 ring atoms, wherein from        1-4 ring atoms are each independently selected from N, N(R^(f)),        O, and S, and which is optionally substituted with from 1-4        R^(g), or    -   (vii) heterocycloalkylene including from 3-10 ring atoms,        wherein from 1-3 ring atoms are each independently selected from        N, N(R^(f)) and O, and which is optionally further substituted        with from 1-4 R^(g).

For example, Y can be interrupted by a heteroatom (e.g., one or more ofO, S, and N(R^(f))). As another example, Y can be interrupted by any of(iv), (v), (vi), or (vii).

In certain embodiments, R² is R⁶.

In any of the foregoing embodiments, R⁶ can be as defined anywhereherein.

In some embodiments, R² is:

(i) —Y—R⁶, wherein:

-   -   Y is C₁₋₈ alkylene, which is optionally substituted with from        1-4 R^(e); and    -   R⁶ is —OH; -OBn; —O(C₁₋₄ alkyl), —C(O)R^(a); —CO₂R^(a);        —CONR′R″; —NR^(b)R^(c); cyano; -OBn, wherein the phenyl portion        is optionally substituted with from 1-3 R^(d); or heteroaryl        including from 5-6 ring atoms, wherein from 1-4 ring atoms are        each independently selected from N, N(R^(f)), O, and S, wherein        the heteroaryl is optionally substituted with from 1-3 R^(d);

OR

(ii) —C(O)—Y—R⁶;

OR

(iii) —R⁶;

OR

(iv) —(Y′)—Y²—(Y³)_(p)—R^(6′), wherein:

-   -   each of n and p is independently 0 or 1;    -   each of Y¹ and Y³ is, independently, C₁₋₃ alkylene, which is        optionally substituted with from 1-2 R^(e),    -   Y² is:        -   (a) C₃₋₆ cycloalkylene optionally substituted with from 1-4            R^(g),        -   (b) C₆₋₁₀ arylene, optionally further substituted with from            1-4 R^(d),        -   (c) heteroarylene including from 5-10 ring atoms, wherein            from 1-4 ring atoms are each independently selected from N,            N(R^(f)), O, and S, and which is optionally further            substituted with from 1-4 R^(g), or        -   (d) heterocycloalkylene including from 3-10 ring atoms,            wherein from 1-3 ring atoms are each independently selected            from N, N(R^(f)) and O, and wherein Y² is optionally further            substituted with from 1-4 R^(g), and    -   R^(6′) is H, —OH, —C(O)R^(a), —CO₂R^(a); —CONR′R″, —NR^(b)R^(c),        cyano, or heteroaryl including from 5-6 ring atoms, wherein from        1-4 ring atoms are each independently selected from N, N(R^(f)),        O, and S, wherein R^(6′) cannot be H when Y² is C₃₋₆        cycloalkylene optionally substituted with from 1-4 R^(g) or when        Y² is C₆₋₁₀ arylene, optionally substituted with from 1-4 R^(d),

OR

(v) —Z¹—Z²—Z³—R⁷, wherein:

-   -   Z¹ is C₁₋₃ alkylene, which is optionally substituted with from        1-6 F,    -   Z² is —N(R^(f))—, —O—, or —S—;    -   Z³ is C₂₋₅ alkylene, which is optionally substituted with from        1-6 F, and    -   R⁷ is —OH, —C(O)R^(a), CO₂R^(a); —CONR′R″, —NR^(b)R^(c), or        heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring        atoms are each independently selected from N, N(R^(f)), O, and        S, wherein the heteroaryl is optionally substituted with from        1-3 R^(d).

In some embodiments, R² is:

(i) —Y—R⁶, wherein:

-   -   Y is C₁₋₈ alkylene, which is optionally substituted with from        1-4 R^(e); and    -   R⁶ is —OH; -OBn; —O(C₁₋₄ alkyl), —C(O)R^(a); —CO₂R^(a);        —CONR′R″; —NR^(b)R^(c); cyano; -OBn, wherein the phenyl portion        is optionally substituted with from 1-3 R^(d); or heteroaryl        including from 5-6 ring atoms, wherein from 1-4 ring atoms are        each independently selected from N, N(R^(f)), O, and S, wherein        the heteroaryl is optionally substituted with from 1-3 R^(d);

OR

(ii) —C(O)—Y—R⁶;

OR

(iii) —R⁶;

OR

(iv) —(Y¹)_(n)—Y²—(Y³)_(p)—R^(6′), wherein:

-   -   each of n and p is independently 0 or 1;    -   each of Y¹ and Y³ is, independently, C₁₋₃ alkylene, which is        optionally substituted with from 1-2 R^(e),    -   Y² is:        -   (a) C₃₋₆ cycloalkylene optionally substituted with from 1-4            R^(g),        -   (b) C₆₋₁₀ arylene, optionally further substituted with from            1-4 R^(d),        -   (c) heteroarylene including from 5-10 ring atoms, wherein            from 1-4 ring atoms are each independently selected from N,            N(R^(f)), O, and S, and which is optionally further            substituted with from 1-4 R^(g), or        -   (d) heterocycloalkylene including from 3-10 ring atoms,            wherein from 1-3 ring atoms are each independently selected            from N, N(R^(f)) and O, and wherein Y² is optionally further            substituted with from 1-4 R^(g), and    -   R^(6′) is H, —OH, —C(O)R^(a), —CO₂R^(a); —CONR′R″, —NR^(b)R^(c),        cyano, or heteroaryl including from 5-6 ring atoms, wherein from        1-4 ring atoms are each independently selected from N, N(R^(f)),        O, and S, wherein R^(6′) cannot be H when Y² is C₃₋₆        cycloalkylene optionally substituted with from 1-4 R^(g) or when        Y² is C₆₋₁₀ arylene, optionally substituted with from 1-4 R^(d).

In some embodiments, R² is:

(i) —Y—R⁶, wherein:

-   -   Y is C₁₋₈ alkylene, which is optionally substituted with from        1-4 R^(e); and    -   R⁶ is —OH; -OBn; —O(C₁₋₄ alkyl), —C(O)R^(a); —CO₂R^(a);        —CONR′R″; —NR^(b)R^(c); cyano; -OBn, wherein the phenyl portion        is optionally substituted with from 1-3 R^(d); or heteroaryl        including from 5-6 ring atoms, wherein from 1-4 ring atoms are        each independently selected from N, N(R^(f)), O, and S, wherein        the heteroaryl is optionally substituted with from 1-3 R^(d);

OR

(ii) —C(O)—Y—R⁶;

OR

(iii) —R⁶;

In some embodiments, R² is:

(i) —Y—R⁶, wherein:

-   -   Y is C₁₋₈ alkylene, which is optionally substituted with from        1-4 R^(e); and    -   R⁶ is —OH, C(O)R^(a), CO₂R^(a), —CONR^(b)R^(c), —NR^(b)R^(c), or        heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring        atoms are each independently selected from N, N(R^(f)), O, and        S, wherein the heteroaryl is optionally substituted with from        1-3 R^(d).

OR

(ii) —C(O)—Y—R⁶, wherein Y and R⁶ are as defined above in (i);

OR

(iii) —R⁶.

In some embodiments, R² is:

(i) —Y—R⁶, wherein:

-   -   Y is C₁₋₈ alkylene, which is optionally substituted with from        1-4 R^(e); and    -   R⁶ is —OH, C(O)R^(a), CO₂R^(a), —CONR^(b)R^(c), —NR^(b)R^(c), or        heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring        atoms are each independently selected from N, N(R^(f)), O, and        S, wherein the heteroaryl is optionally substituted with from        1-3 R^(d);

OR

(ii) —C(O)—Y—R⁶, wherein Y and R⁶ are as defined above in (i).

—Y—R⁶

In some embodiments, R² is:

(i) —Y—R⁶, wherein:

-   -   Y is C₁₋₈ alkylene, which is optionally substituted with from        1-4 R^(e); and    -   R⁶ is —OH, C(O)R^(a), CO₂R^(a), —CON^(b)R^(c), —NR^(b)R^(c), or        heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring        atoms are each independently selected from N, N(R^(f)), O, and        S, wherein the heteroaryl is optionally substituted with from        1-3 R^(d);

In some embodiments, R² is Y—R⁶, wherein:

-   -   Y is C₂₋₈ alkylene, which is optionally substituted with from        1-4 R^(e); and    -   R⁶ is —OH, C(O)R^(a), CO₂R^(a); —CONR^(b)R^(c), —NR^(b)R^(c), or        heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring        atoms are each independently selected from N, N(R^(f)), O, and        S.

In some embodiments, Y is an unbranched C₁₋₈ alkylene (e.g., C₁₋₄alkylene), which is optionally substituted with from 1-4 (e.g., 1-2, 1)R^(e).

In some embodiments, Y is an unbranched C₁₋₈ alkylene, which isunsubstituted.

In some embodiments, Y is CH₂.

In some embodiments, Y is an unbranched C₂₋₆ (e.g., C₂₋₄, C₂₋₃, C₂)alkylene, which is optionally substituted with from 1-4 (e.g., 1-2, 1)R^(e). In certain embodiments, Y is an unbranched C₂₋₆ (e.g., C₂₋₄,C₂₋₃, C₂) alkylene, which is unsubstituted (e.g., C₂ alkylene or C₃alkylene; e.g., C₃ alkylene).

In other embodiments, Y is branched C₃₋₆ (e.g., C₄₋₆, C₅₋₆) alkylene,which is optionally substituted with from 1-4 (e.g., 1-2, 1) R^(e). Incertain embodiments, Y has the formula, R—CH(CH₃)—R⁶, in which R is C₁₋₄alkylene. In certain embodiments, Y is a branched C₂₋₃ alkylene. Incertain embodiments, Y is a C₂ alkylene with the formula —CH(CH₃)—. Incertain embodiments, Y is a C₃ alkylene with the formula —C(CH₃)₂—.

In some embodiments, R⁶ is —OH, CO₂R^(a); -or —NR^(b)R^(c). In someembodiments, R⁶ is —OH or —NR^(b)R^(c).

In certain embodiments, R⁶ is —OH. In certain embodiments, R⁶ is -OBn.In certain embodiments, R⁶ is —O(C₁₋₄ alkyl).

In certain embodiments, R⁶ is —NR^(b)R^(c).

In certain of these embodiments, each occurrence of R^(b) and R^(c) isindependently selected from: H; R^(a); —C(O)(R^(a)), —C(O)O(R^(a)),—S(O)₁₋₂(R^(h)), —C(O)NR′R″, and —S(O)₁₋₂(NR′R″).

In certain of these embodiments, each occurrence of R^(b) and R^(c) isindependently selected from: H; R^(a); —C(O)(R^(a)), —C(O)O(R^(a)), and—C(O)NR′R″.

In certain of these embodiments, each occurrence of R^(b) and R^(c) isindependently selected from: H; R^(a); —S(O)₁₋₂(R^(h)), and—S(O)₁₋₂(NR′R″).

In certain of these embodiments, each occurrence of R^(b) and R^(c) isindependently selected from: H; R^(a); and —C(O)(R^(a)).

In certain of these embodiments, one of R^(b) and R^(c) is —C(O)(R^(a));and the other is H or R^(a).

In certain of these embodiments, each occurrence of R^(b) and R^(c) isindependently selected from: H, C₁₋₄ alkyl, and —C(O)(C₁₋₄ alkyl).

In certain of these embodiments, one of R^(b) and R^(c) is —C(O)(C₁₋₄alkyl) (e.g., —C(O)CH₃); and the other is H or C₁₋₄ alkyl (e.g.,CH₂CH₃).

In certain of these embodiments, each occurrence of R^(b) and R^(c) isindependently selected from: H, C₁₋₄ alkyl, —C(O)(C₁₋₄ alkyl),—C(O)O(C₁₋₄ alkyl), —S(O)₁₋₂(R^(h)), —C(O)NR^(j)R^(k), —OH, and C₁₋₄alkoxy.

In certain of these embodiments, each occurrence of R^(b) and R^(c) isindependently selected from: H, C₁₋₄ alkyl, —C(O)(C₁₋₄ alkyl),—C(O)O(C₁₋₄ alkyl), —S(O)₁₋₂(R^(h)), and —C(O)NR^(j)R^(k).

In certain of these embodiments, each occurrence of R^(b) and R^(c) isindependently selected from: H, C₁₋₄ alkyl, and —C(O)(C₁₋₄ alkyl).

In certain of these embodiments, each occurrence of R^(b) and R^(c) isindependently selected from: H and C₁₋₄ alkyl. For example, R⁶ can be—NH₂, —N(H)(C₁₋₄ alkyl) (e.g., —NHCH₃) or —N(C₁₋₄ alkyl)₂ (e.g.,—N(CH₃)₂).

In certain of these embodiments, each occurrence of R^(b) and R^(c) isindependently selected from: H and —C(O)(C₁₋₄ alkyl). For example, oneof R^(b) and R^(c) is H, and the other is —C(O)(C₁₋₄ alkyl) (e.g.,—C(O)(CH₃).

In certain of these embodiments, each occurrence of R^(b) and R^(c) isindependently selected from: C₁₋₄ alkyl and —C(O)(C₁₋₄ alkyl). Forexample, one of R^(b) and R^(c) is C₁₋₄ alkyl (e.g., CH₃), and the otheris —C(O)(C₁₋₄ alkyl) (e.g., —C(O)(CH₃).

In certain embodiments, R⁶ is CO₂R^(a).

In certain of these embodiments, R^(a) is C₁₋₆ alkyl optionallysubstituted with —OH, —NH₂, —NH(C₁₋₃ alkyl), —N(C₁₋₃ alkyl)₂,—N(H)(C(═O)C₁₋₃ alkyl), or cyano.

In certain of these embodiments, R^(a) is unsubstituted C₁₋₆ alkyl(e.g., CH₃ or CH₂CH₃).

In certain embodiments, R⁶ is —OH (in certain embodiments, R² is—CH₂CH₂CH₂OH).

In some embodiments, R² has formula (R2-A)

wherein:

R⁸ and R⁹, are defined according to (1) or (2) below:

(1):

R⁸ is independently selected from: H; C₁₋₈ (e.g., C₁₋₆) alkyl optionallysubstituted with from 1-2 independently selected R^(e); —C(O)(R^(a));—C(O)O(R^(a)); —S(O)₁₋₂(R^(h)); —C(O)NR′R″; and —S(O)₁₋₂(NR′R″);

R⁹ is independently selected from: H and C₁₋₆ alkyl optionallysubstituted with from 1-2 independently selected R^(e); and

OR

(2):

R⁸ and R⁹, together with the nitrogen atom to which each is attachedforms a saturated ring including from 3-10 ring atoms, wherein the ringincludes:

(a) from 1-9 ring carbon atoms, each of which is substituted with from1-2 substituents independently selected from H and R^(g), and

(b) from 0-3 ring heteroatoms (in addition to the nitrogen atom attachedto R⁸ and R⁹), each of which is independently selected from N, N(R^(f)),O, and S; and

each of R¹⁰ and R¹¹ is independently selected from: H and unsubstitutedC₁₋₂ alkyl; or R¹⁰ and R¹¹ together with the carbon atom to which eachis attached, forms a C₃-C₅ cycloalkyl, optionally substituted with from1-4 independently selected R^(g).

In some embodiments, R⁸ and R⁹ are defined according to (1).

In some embodiments, R⁸ is independently selected from: —C(O)(R^(a));—C(O)O(R^(a)); —S(O)₁₋₂(R^(h)); —C(O)NR′R″; and —S(O)₁₋₂(NR′R″).

In some embodiments, R^(a) is C₁₋₆ alkyl optionally substituted withfrom 1-2 independently selected R^(e).

In certain embodiments, R^(a) is unsubstituted C₁₋₆ alkyl.

In some embodiments, R^(a) is selected from CH₃, CH₂CH₃, andunsubstituted, unbranched C₃₋₆ alkyl. In some embodiments, R^(a) is CH₃or CH₂CH₃.

In some embodiments, R^(a) is unsubstituted, branched C₃₋₆ alkyl. Insome embodiments, R^(a) is iso-propyl.

In some embodiments, R^(a) is —(C₀₋₆ alkylene)-C₃₋₁₀ cycloalkyl, whereinthe cycloalkyl is optionally substituted with from 1-4 independentlyselected R^(g);

In some embodiments, R^(a) is C₃₋₁₀ (e.g., C₃₋₈ or C₃₋₆) cycloalkyl,wherein the cycloalkyl is optionally substituted with from 1-4independently selected R^(g);

In some embodiments, R^(a) is unsubstituted C₃₋₁₀ (e.g., C₃₋₈ or C₃₋₆)cycloalkyl. In some embodiments, the cycloalkyl is cyclopropyl.

In some embodiments, R^(a) is —(C₀₋₆ alkylene)-heteroaryl including from5-10 ring atoms, wherein from 1-4 ring atoms are each independentlyselected from N, N(R^(f)), O, and S, wherein the heteroaryl isoptionally substituted with from 1-3 independently selected R^(d).

In some embodiments, R^(a) is heteroaryl including from 5-10 ring atoms,wherein from 1-4 ring atoms are each independently selected from N,N(R^(f)), O, and S, wherein the heteroaryl is optionally substitutedwith from 1-3 independently selected R^(d).

In some embodiments, R⁸ is —S(O)₁₋₂(R^(h)). In some embodiments, R^(h)is C₁₋₆ alkyl. In some embodiments, R^(h) is CH₃.

In some embodiments, R⁸ is —C(O)NR′R″.

In some embodiments, each of R′ and R″ is independently selected from: Hand C₁₋₄ alkyl.

In some embodiments, R^(g) is unsubstituted C₁₋₆ alkyl. In someembodiments, R⁸ is selected from CH₃, CH₂CH₃, and unsubstituted,unbranched C₃₋₆ alkyl. In some embodiments, R⁸ is CH₃ or CH₂CH₃.

In some embodiments, R⁸ is H.

In some embodiments, R⁹ is unsubstituted C₁₋₈ alkyl. In someembodiments, R⁹ is selected from CH₃, CH₂CH₃, and unsubstituted,unbranched C₃₋₆ alkyl. In some embodiments, R⁹ is CH₃ or CH₂CH₃.

In some embodiments, R⁹ is H.

In some embodiments, R⁸ and R⁹ are defined according to (2).

In some embodiments, R⁸ and R⁹, together with the nitrogen atom to whicheach is attached forms a saturated ring including from 4-7 (e.g., 5-6)ring atoms, wherein the ring includes:

(a) from 1-6 (e.g., 1-5) ring carbon atoms, each of which is substitutedwith from 1-2 substituents independently selected from H and R^(g), and

(b) from 0-2 ring heteroatoms, each of which is independently selectedfrom N, N(R^(f)), O, and S; and

provided that one ring atom is —C(O)—.

In some embodiments, —C(R¹⁰)(R¹¹)—NR⁸R⁹ has the following formula:

In some embodiments, —C(R¹⁰)(R¹¹)—NR⁸R⁹ has the following formula:

wherein:

A₁ is a bond, C(O), CH₂, CHR^(g), or C(R^(g))₂;

A₂ is C(O), CH₂, CHR^(g), or C(R^(g))₂;

A₃ is C(O), CH₂, CHR^(g), or C(R^(g))₂; or N(R^(f));

A₄ is CH₂, CHR^(g), or C(R^(g))₂; or N(R^(f)); provided that both A₃ andA₄ cannot both be N(R^(f)).

In some embodiments, —C(R¹⁰)(R¹¹)—NR⁸R⁹ has the following formula:

wherein:

A₁ is a bond, C(O), CH₂, CHR^(g), or C(R^(g))₂;

A₂ is C(O), CH₂, CHR^(g), or C(R^(g))₂; and

A₃ is CH₂, CHR^(g), or C(R^(g))₂; or N(R^(f)).

In some embodiments, A₁ is a bond.

In some embodiments, each of A₂ and A₄ is independently selected fromCH₂, CHR^(g), and C(R^(g))₂.

In some embodiments, each of A₂ and A₄ is CH₂.

In some embodiments, A₃ is CH₂ or CHR^(g).

In some embodiments, R^(g) is C₁₋₄ alkyl, —OH, C₁₋₄ alkoxy, C₁₋₄haloalkoxy, heteroaryl including from 5-10 ring atoms, wherein from 1-4ring atoms are each independently selected from N, N(R^(f)), O, and S,wherein the heteroaryl is optionally substituted with from 1-3 R^(m);and phenyl optionally substituted with from 1-4 R^(m).

In some embodiments, each of R¹⁰ and R¹¹ is H.

In some embodiments:

R⁸ is independently selected from: —C(O)(R^(a)); —C(O)O(R^(a));—S(O)₁₋₂(R^(h)); —C(O)NR′R″; and —S(O)₁₋₂(NR′R″) (as defined anywhereherein); and R⁹ is unsubstituted C₁₋₆ alkyl (as defined anywhere herein;e.g., CH₃, CH₂CH₃, and unsubstituted, unbranched C₃₋₆ alkyl; e.g., CH₃,CH₂CH₃); or

R⁸ is independently selected from: —C(O)(R^(a)); —C(O)O(R^(a));—S(O)₁₋₂(R^(h)); —C(O)NR′R″; and —S(O)₁₋₂(NR′R″) (as defined anywhereherein); and R⁹ is H; or

R⁸ is unsubstituted C₁₋₆ alkyl (as defined anywhere herein); and R⁹ isunsubstituted C₁₋₆ alkyl (as defined anywhere herein; e.g., CH₃, CH₂CH₃,and unsubstituted, unbranched C₃₋₆ alkyl; e.g., CH₃, CH₂CH₃); or

R⁸ is unsubstituted C₁₋₆ alkyl (as defined anywhere herein; e.g., CH₃,CH₂CH₃, and unsubstituted, unbranched C₃₋₆ alkyl; e.g., CH₃, CH₂CH₃);and R⁹ is H; or

R⁸ is H; and R⁹ is H.

In some embodiments, R⁸ is —C(O)(R^(a)) (e.g., R^(a) is C₁₋₆ alkyloptionally substituted with from 1-2 independently selected R^(e) e.g.,R^(e) is unsubstituted C₁₋₆ alkyl; e.g., R^(e) is selected from CH₃,CH₂CH₃, and unsubstituted, unbranched C₃₋₆ alkyl; e.g., R^(e) is CH₃ orCH₂CH₃).

In some embodiments, each of R¹⁰ and R¹¹ is H.

In some embodiments, R² is

wherein:

R⁶ is independently selected from: —OH, —O(C₁₋₄ alkyl), —CO₂R^(a),—C(O)NR′R′; and heteroaryl including from 5-6 ring atoms, wherein from1-3 ring atoms are each independently selected from N, N(R^(f)), O, andS, wherein the heteroaryl is optionally substituted with from 1-3 R^(d);

In certain embodiments, R⁶ is —OH.

In certain embodiments, R⁶ is —O(C₁₋₄ alkyl). For example, R¹² ismethoxy or ethoxy.

In certain embodiments, R⁶ is —C(O)R^(a).

In certain embodiments, R^(a) is C₁₋₆ alkyl optionally substituted withfrom 1-2 independently selected R^(e). In certain embodiments, R^(a) isunsubstituted C₁₋₆ alkyl. For example, R^(a) can be selected from CH₃,CH₂CH₃, and unsubstituted, unbranched C₃₋₆ alkyl (e.g., CH₃ or CH₂CH₃).As another example, R^(a) can be unsubstituted, branched C₃₋₆ alkyl(e.g., iso-propyl).

In other embodiments, R^(a) is —(C₀₋₆ alkylene)-C₃₋₁₀ cycloalkyl,wherein the cycloalkyl is optionally substituted with from 1-4independently selected R^(g). For example, R^(a) can be C₃₋₁₀ (e.g.,C₃₋₈ or C₃₋₆) cycloalkyl, wherein the cycloalkyl is optionallysubstituted with from 1-4 independently selected R^(g); e.g., R^(a) canbe unsubstituted C₃₋₁₀ (e.g., C₃₋₈ or C₃₋₆ or C₃₋₅ or C₃₋₄) cycloalkyl.In each of the foregoing embodiments, the cycloalkyl is cyclopropyl.

In still other embodiments, R^(a) is —(C₀₋₆ alkylene)-heteroarylincluding from 5-10 ring atoms, wherein from 1-4 ring atoms are eachindependently selected from N, N(R^(f)), O, and S, wherein theheteroaryl is optionally substituted with from 1-3 independentlyselected R^(d). For example, R^(a) can be heteroaryl including from 5-10ring atoms, wherein from 1-3 ring atoms are each independently selectedfrom N, N(R^(f)), O, and S, wherein the heteroaryl is optionallysubstituted with from 1-3 independently selected R^(d).

In certain embodiments, R⁶ is —C(O)NR′R′. In certain of theseembodiments, each of R′ and R′ is independently selected from: H andC₁₋₄ alkyl.

—(Y¹)_(n)—Y²—(Y³)_(p)—R⁶′

In some embodiments, R² is —(Y¹)_(n)—Y²—(Y³)_(p)—R^(6′), wherein:

-   -   each of n and p is independently 0 or 1;    -   each of Y¹ and Y³ is, independently, C₁₋₃ alkylene, which is        optionally substituted with from 1-2 R^(e),    -   Y² is:        -   (a) C₃₋₆ cycloalkylene optionally substituted with from 1-4            R^(g),        -   (b) C₆₋₁₀ arylene, optionally further substituted with from            1-4 R^(d),        -   (c) heteroarylene including from 5-10 ring atoms, wherein            from 1-4 ring atoms are each independently selected from N,            N(R^(f)), O, and S, and which is optionally further            substituted with from 1-4 R^(g), or        -   (d) heterocycloalkylene including from 3-8 ring atoms,            wherein from 1-2 ring atoms are each independently selected            from N, N(R^(f)) and O, and wherein Y² is optionally further            substituted with from 1-4 R^(g), and    -   R^(6′) is H, —OH, —C(O)R^(a), —CO₂R^(a); —CONR′R″, —NR^(b)R^(c),        or heteroaryl including from 5-6 ring atoms, wherein from 1-4        ring atoms are each independently selected from N, N(R^(f)), O,        and S, wherein R^(6′) cannot be H when Y² is C₃₋₆ cycloalkylene        optionally substituted with from 1-4 R⁹ or when Y² is C₆₋₁₀        arylene, optionally substituted with from 1-4 R^(d).

In some embodiments, R² is —(Y¹)_(n)—Y²—(Y³)_(p)—R^(6′), wherein:

-   -   each of n and p is independently 0 or 1;    -   each of Y¹ and Y³ is, independently, C₁₋₃ alkylene, which is        optionally substituted with from 1-2 R^(e),    -   Y² is C₃₋₆ cycloalkylene C₆₋₁₀ aryl, heteroaryl including from        5-10 ring atoms, wherein from 1-4 ring atoms are each        independently selected from N, N(R^(e)), O, and S, or        heterocycloalkylene including from 3-8 ring atoms, wherein from        1-2 ring atoms are each independently selected from N, N(R^(f))        and oxygen, and wherein Y² is optionally further substituted        with from 1-4 R^(g), and    -   R^(6′) is H, —OH, CO₂R^(a); —CONR^(b)R^(c), —NR^(b)R^(c), or        heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring        atoms are each independently selected from N, N(R^(f)), O, and        S.

In some embodiments, R² is —(Y¹)_(n)—Y²—(Y³)_(p)—R^(6′), wherein:

-   -   each of n and p is independently 0 or 1;    -   each of Y¹ and Y³ is, independently, C₁₋₃ alkylene, which is        optionally substituted with from 1-2 R^(e),    -   Y² is C₃₋₆ cycloalkylene or heterocycloalkylene including from        3-8 ring atoms, wherein from 1-2 ring atoms are each        independently selected from N, N(R^(f)) and oxygen, and wherein        Y² is optionally further substituted with from 1-4 R, and    -   R^(6′) is H, —OH, CO₂R^(a); —CONR^(b)R^(c), —NR^(b)R^(c), or        heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring        atoms are each independently selected from N, N(R^(f)), O, and        S, wherein R^(6′) cannot be H when Y² is C₃₋₆ cycloalkylene        optionally substituted with from 1-4 R^(g);

In some embodiments, n is 0.

In some embodiments, n is 1. In certain of these embodiments, Y¹ is CH₂.

In some embodiments, Y² is C₃₋₆ (e.g., C₃₋₅, C₃₋₄) cycloalkyleneoptionally substituted with from 1-4 R^(g). In certain embodiments, p is0. In certain embodiments, p is 1; in certain of these embodiments, Y³is C₁₋₂ alkylene.

In some embodiments, Y² is C₆₋₁₀ aryl (e.g., phenyl).

In some embodiments, Y² is heteroaryl including from 5-10 ring atoms,wherein from 1-4 ring atoms are each independently selected from N,N(R^(e)), O, and S.

In some embodiments, Y² is pyrrole, pyrazole, 1,2,3-triazole, thiophene,or thiazole.

In some embodiments, Y² is heterocycloalkylene including from 3-8 (e.g.,5-8, 6-8, 7-8, 4-6, 5-6) ring atoms, wherein from 1-2 (e.g., 1) ringatoms are each independently selected from N, N(R^(f)), and oxygen, andwherein Y² is optionally further substituted with from 1-4 R^(g).

In some embodiments, Y² is heterocycloalkylene including from 3-8 ringatoms, wherein from 1-2 ring atoms are each independently selected fromN and N(R^(f)), and wherein Y² is optionally further substituted withfrom 1-4 R^(g).

In some embodiments, Y² is heterocycloalkylene including from 3-8 ringatoms, wherein 1 ring atom is N(R^(f)), and wherein Y² is optionallyfurther substituted with from 1-4 R^(g).

In some embodiments, Y² is heterocycloalkylene including from 3-8 ringatoms, wherein 1 ring atom is N, and wherein Y² is optionally furthersubstituted with from 1-4 R^(g).

In some embodiments, Y² is heterocycloalkylene including from 3-6 (e.g.,4-6, 5-6) ring atoms, wherein from 1-2 (e.g., 1) ring atoms are eachindependently selected from N, N(R^(f)), and oxygen, and wherein Y² isoptionally further substituted with from 1-4 R^(g).

In certain embodiments, Y² is heterocycloalkylene including from 3-6(e.g., 4-6, 5-6) ring atoms, wherein from 1-2 ring atoms are eachindependently selected from N and N(R^(f)), and wherein Y² is optionallyfurther substituted with from 1-4 R^(g).

In certain embodiments, Y² is heterocycloalkylene including from 3-6(e.g., 4-6, 5-6) ring atoms, wherein 1 ring atom is N(R^(f)), andwherein Y² is optionally further substituted with from 1-4 R^(g).

In certain embodiments, Y² is heterocycloalkylene including from 3-6(e.g., 4-6, 5-6) ring atoms, wherein 1 ring atom is N, and wherein Y² isoptionally further substituted with from 1-4 R^(g). In certain of theseembodiments, the ring atom N is attached to Y, when present, or the5-membered heteroaromatic ring of formula (I). In other of theseembodiments, the ring atom N is attached to Y³, when present, or R⁶. Incertain embodiments, p is 0. In certain embodiments, p is 1; in certainof these embodiments, Y³ is C₂₋₃ alkylene. In still other embodiments,the ring atom N is attached to the imidazole ring of formula (I). Instill other embodiments, the ring atom N is attached to R⁶. In anotherembodiment, n is 0, p is 0, and the ring atom N is attached to R⁶.

In some embodiments, each occurrence of R^(f) is independently selectedfrom H; C₁₋₄ alkyl; C₃₋₆ cycloalkyl; and phenyl; wherein each C₁₋₄ alkylis optionally substituted with from 1-2 independently selected R^(e);each C₃₋₆ cycloalkyl is optionally substituted with from 1-2independently selected R^(g); and each phenyl is optionally substitutedwith from 1-2 independently selected R^(d).

In some —(Y¹)_(n)—Y²—(Y³)_(p)—R^(6′) embodiments, R^(6′) can be asdefined above in conjunction with variable Y. In certain embodiments,R^(6′) can be H.

In some embodiments, Y² is further substituted with from 1-4 R^(g).

In some embodiments, Y² is further substituted with from 1-2 R^(g).

In some embodiments, each occurrence of R⁹ is independently selectedfrom: C₁₋₆ alkyl optionally substituted with from 1-2 independentlyselected R^(e); C₁₋₄ haloalkyl; oxo; heteroaryl including from 5-10 ringatoms, wherein from 1-4 ring atoms are each independently selected fromN, N(R^(f)), O, and S, wherein the heteroaryl is optionally substitutedwith from 1-3 R^(m); and phenyl optionally substituted with from 1-4R^(m).

In some embodiments, one R^(g) is oxo.

In certain embodiments, p is 0.

In certain embodiments, p is 1.

In some embodiments, Y³ is C₂₋₃ alkylene.

In some embodiments, Y² is C₃₋₆ cycloalkylene optionally substitutedwith from 1-4 R^(g).

In certain embodiments, p is 0.

In certain embodiments, p is 1.

In some embodiments, Y³ is C₁₋₂ alkylene.

In some embodiments, Y² is C₆₋₁₀ arylene (e.g., phenylene).

In certain embodiments, p is 0.

In certain embodiments, p is 1.

In some embodiments, Y³ is C₂₋₃ alkylene.

In some embodiments, Y² is heteroarylene including from 5-10 ring atoms,wherein from 1-4 ring atoms are each independently selected from N,N(R^(e)), O, and S.

In some embodiments, Y² is pyrrolylene, pyrazolylene,1,2,3-triazolylene, thienylene, or thiazolylene.

In certain embodiments, p is 0.

In certain embodiments, p is 1.

In some embodiments, Y³ is C₂₋₃ alkylene.

In some embodiments, R^(6′) is H, —OH, CO₂R^(a); -or —NR^(b)R^(c).

In some embodiments, R^(6′) is H.

In some embodiments, R^(6′) is CO₂R′.

In some embodiments, R^(a) is C₁₋₆ alkyl optionally substituted with—OH, —NH₂, —NH(C₁₋₃ alkyl), —N(C₁₋₃ alkyl)₂, —N(H)(C(═O)C₁₋₃ alkyl), orcyano.

In some embodiments, R^(a) is unsubstituted C₁₋₆ alkyl.

In some embodiments, R^(a) is CH₃ or CH₂CH₃.

In some embodiments, R^(6′) is —OH.

In some embodiments, R^(6′) is —NR^(b)R^(c).

In some embodiments, each occurrence of R^(b) and R^(c) is independentlyselected from: H; R^(a); and —C(O)(R^(a)).

In some embodiments, one of R^(b) and R^(c) is —C(O)(R^(a)); and theother is H or R^(a).

In some embodiments, each occurrence of R^(b) and R^(c) is independentlyselected from: H, C₁₋₄ alkyl, and —C(O)(C₁₋₄ alkyl).

In some embodiments, one of R^(b) and R^(c) is —C(O)(C₁₋₄ alkyl) (e.g.,—C(O)CH₃); and the other is H or C₁₋₄ alkyl (e.g., CH₂CH₃).

In some embodiments, R^(6′) is —OH.

In some embodiments, R^(6′) is —NR^(b)R^(c).

In some embodiments, each occurrence of R^(b) and R^(c) is independentlyselected from: H; R^(a); and —C(O)(R^(a)).

In some embodiments, one of R^(b) and R^(c) is —C(O)(R^(a)); and theother is H or R^(a).

In some embodiments, each occurrence of R^(b) and R^(c) is independentlyselected from: H, C₁₋₄ alkyl, and —C(O)(C₁₋₄ alkyl).

In some embodiments, one of R^(b) and R^(c) is —C(O)(C₁₋₄ alkyl) (e.g.,—C(O)CH₃); and the other is H or C₁₋₄ alkyl (e.g., CH₂CH₃).

—Z¹—Z²—Z³—R⁷

In some embodiments, R² is —Z¹—Z²—Z³—R⁷, wherein:

-   -   Z¹ is C₁₋₃ alkylene, which is optionally substituted with from        1-6 F,    -   Z² is —N(R^(f))—, —O—, or —S—;    -   Z³ is C₂₋₅ alkylene, which is optionally substituted with from        1-6 F, and    -   R⁷ is —OH, —C(O)R^(a), CO₂R^(a); —CONR′R″, —NR^(b)R^(c), or        heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring        atoms are each independently selected from N, N(R^(f)), O, and        S, wherein the heteroaryl is optionally substituted with from        1-3 R^(d).

In some embodiments, R² is —Z¹—Z²—Z³—R⁷, wherein:

-   -   Z¹ is an unbranched or branched C₁₋₃ alkylene, which is        optionally substituted with from 1-6 F,    -   Z² is —N(R^(f))—, —O—, or —S—;    -   Z³ is an unbranched or branched C₂₋₅ alkylene, which is        optionally substituted with from 1-6 F, and    -   R⁷ is —OH, —C(O)R^(a), CO₂R^(a); —CONR^(b)R^(c), —NR^(b)R^(c),        or heteroaryl including from 5-6 ring atoms, wherein from 1-4        ring atoms are each independently selected from N, N(R^(f)), O,        and S;

In some embodiments, Z¹ is CH₂.

In some embodiments, Z² is —O—, or —S— (e.g., —O—).

In some embodiments, Z² is —N(R^(f))—. For example, Z² can be —NH—,—N(C₁₋₄ alkyl)-, or —NC(O)(C₁₋₄ alkyl)- (e.g., —NC(O)(CH₃)—).

In some embodiments, Z³ is C₂₋₃ alkylene.

In some embodiments, R⁷ is —OH, CO₂R^(a); -or —NR^(b)R^(c).

In certain embodiments, R⁷ is —NR^(b)R^(c).

In certain of these embodiments, each occurrence of R^(b) and R^(c) isindependently selected from: H; R^(a); —C(O)(R^(a)), —C(O)O(R^(a)),—S(O)₁₋₂(R^(h)), —C(O)NR′R″, and —S(O)₁₋₂(NR′R″).

In certain of these embodiments, each occurrence of R^(b) and R^(c) isindependently selected from: H; R^(a); —C(O)(R^(a)), —C(O)O(R^(a)), and—C(O)NR′R″.

In certain of these embodiments, each occurrence of R^(b) and R^(c) isindependently selected from: H; R^(a); —S(O)₁₋₂(R^(h)), and—S(O)₁₋₂(NR′R″).

In certain of these embodiments, each occurrence of R^(b) and R^(c) isindependently selected from: H; R^(a); and —C(O)(R^(a)).

In certain of these embodiments, one of R^(b) and R^(c) is —C(O)(R^(a));and the other is H or R^(a).

In certain of these embodiments, each occurrence of R^(b) and R^(c) isindependently selected from: H, C₁₋₄ alkyl, and —C(O)(C₁₋₄ alkyl).

In certain of these embodiments, one of R^(b) and R^(c) is —C(O)(C₁₋₄alkyl) (e.g., —C(O)CH₃); and the other is H or C₁₋₄ alkyl (e.g.,CH₂CH₃).

In certain of these embodiments, each occurrence of R^(b) and R^(c) isindependently selected from: C₁₋₄ alkyl and —C(O)(C₁₋₄ alkyl). Forexample, one of R^(b) and R^(c) is C₁₋₄ alkyl (e.g., CH₃), and the otheris —C(O)(C₁₋₄ alkyl) (e.g., —C(O)(CH₃).

In certain embodiments, R⁷ is CO₂R^(a).

In certain of these embodiments, R^(a) is C₁₋₆ alkyl optionallysubstituted with —OH, —NH₂, —NH(C₁₋₃ alkyl), —N(C₁₋₃ alkyl)₂,—N(H)(C(═O)C₁₋₃ alkyl), or cyano.

In certain of these embodiments, R^(a) is unsubstituted C₁₋₆ alkyl(e.g., CH₃ or CH₂CH₃).

In certain embodiments, R⁷ is —OH.

Variables R³ and R⁴

In some embodiments, one of R³ and R⁴ is hydrogen, and the other is asubstituent other than hydrogen.

In some embodiments, R³ is hydrogen, and R⁴ is hydrogen.

In some embodiments, one of R³ and R⁴ (e.g., R³) is:

(ii) halo;

(iii) cyano;

(vi) C₁₋₄ alkyl, optionally substituted with from 1-2 independentlyselected R^(e);

(vii) C₁₋₄ haloalkyl;

(x) Y⁴—(C₁₋₃ alkylene)_(y)-C₅₋₈ cycloalkyl, wherein the cycloalkyl isoptionally substituted with from 1-4 independently selected R^(g)wherein y is 0 or 1; and Y⁴ is a bond, N(R^(f)), O, or S;

(xi) Y⁴—(C₁₋₃ alkylene)_(y)-heterocyclyl including from 5-8 ring atoms,wherein from 1-3 ring atoms are each independently selected fromN(R^(f)), O, and S, wherein the heterocyclyl is optionally substitutedwith from 1-4 independently selected R^(g), wherein y is 0 or 1; and Y⁴is a bond, N(R^(f)), O, or S;

(xii) Y⁴—(C₁₋₃ alkylene)_(y)-C₆₋₁₀ aryl optionally substituted with from1-4 R^(d), wherein y is 0 or 1; and Y⁴ is a bond, N(R^(f)), O, or S;

(xiii) Y⁴—(C₁₋₃ alkylene)_(y)-heteroaryl including from 5-10 ring atoms,wherein from 1-4 ring atoms are each independently selected from N,N(R^(f)), O, and S, wherein the heteroaryl is optionally substitutedwith from 1-3 R^(d), wherein y is 0 or 1; and Y⁴ is a bond, N(R^(f))O,or S;

and the other (e.g., R⁴) is H.

In some embodiments, one of R³ and R⁴ (e.g., R³) is Y⁴—(C₁₋₃alkylene)_(y)-heteroaryl including from 5-10 ring atoms, wherein from1-4 ring atoms are each independently selected from N, N(R^(f)), O, andS, wherein the heteroaryl is optionally substituted with from 1-3 R^(d),wherein y is 0 or 1; and Y⁴ is a bond, N(R^(f)), O, or S; and the other(e.g., R⁴) is H.

In some embodiments, Y⁴ is a bond.

In some embodiments, Y⁴ is S.

In some embodiments, y is 0.

In some embodiments, y is 1.

In some embodiments, one of R³ and R⁴ (e.g., R³) is heteroaryl includingfrom 5-10 ring atoms, wherein from 1-4 ring atoms are each independentlyselected from N, N(R^(f)), O, and S, wherein the heteroaryl isoptionally substituted with from 1-3 R^(d);

and the other (e.g., R⁴) is H.

In some embodiments, one of R³ and R⁴ (e.g., R³) is heteroaryl includingfrom 5-6 ring atoms, wherein from 1-4 ring atoms are each independentlyselected from N, N(R^(f)), O, and S, wherein the heteroaryl isoptionally substituted with from 1-2 R^(d); and the other (e.g., R⁴) isH.

In some embodiments, one of R³ and R⁴ (e.g., R³) is heteroaryl includingfrom 5-6 ring atoms, wherein from 1-4 ring atoms are each independentlyselected from N and N(R^(f)), wherein the heteroaryl is optionallysubstituted with from 1-2 R^(d); and the other (e.g., R⁴) is H.

In some embodiments, one of R³ and R⁴ (e.g., R³) is pyrrolyl,imidazolyl, pyrazolyl, triazolyl, pyridyl, pyrimidinyl, or pyrazinyl,wherein each is optionally substituted with from 1-2 R^(g); and theother (e.g., R⁴) is H.

In some embodiments, one of R³ and R⁴ (e.g., R³) is pyrrolyl,imidazolyl, pyrazolyl, or triazolyl, wherein each is optionallysubstituted with from 1-2 R^(g); and the other (e.g., R⁴) is H.

In some embodiments, one of R³ and R⁴ (e.g., R³) is pyrazolyl,optionally substituted with from 1-2 R^(g); and the other (e.g., R⁴) isH.

In some embodiments, one of R³ and R⁴ (e.g., R³) is N-linked-pyrazolyl,N-linked pyrrolyl, N-linked imidazolyl, N-linked triazolyl, or N-linkedtetrazolyl, optionally substituted with from 1-2 R^(g); and the other(e.g., R⁴) is H.

In some embodiments, one of R³ and R⁴ (e.g., R³) is C-linked-pyrazolyl,C-linked pyrrolyl (e.g., 3-pyrrolyl), C-linked imidazolyl, C-linkedtriazolyl, or C-linked tetrazolyl, optionally substituted with from 1-2R^(g); and the other (e.g., R⁴) is H.

In some embodiments, one of R³ and R⁴ (e.g., R³) is Y⁴—(C₁₋₃alkylene)_(y)-C₆₋₁₀ aryl optionally substituted with from 1-4 R^(d),wherein y is 0 or 1; and Y⁴ is a bond, N(R^(f)), O, or S; and the other(e.g., R⁴) is H.

In some embodiments, one of R³ and R⁴ (e.g., R³) is Y⁴—(C₁₋₃alkylene)_(y)-heterocyclyl including from 5-8 ring atoms, wherein from1-3 ring atoms are each independently selected from N(R^(f)), O, and S,wherein the heterocyclyl is optionally substituted with from 1-4independently selected R^(d), wherein y is 0 or 1; and Y⁴ is a bond,N(R^(f)), O, or S

Variable R¹

In some embodiments, R¹ is hydrogen.

In some embodiments, R¹ is X—R⁵.

In certain embodiments, X is optionally substituted C₁₋₁₀ alkylene. Inother embodiments, X is unsubstituted C₁₋₁₀ alkylene. In certain of theforegoing embodiments, X is unbranched. In other of the foregoingembodiments, X is branched.

In certain embodiments, X is an unbranched C₁₋₆ alkylene, and R⁵ ishydrogen, —OH, C₁₋₄ alkoxy, —C₁₋₄ haloalkoxy, CO₂R^(a); —CONR′R′, cyano,or —NR^(b)R^(c).

In certain embodiments, X is an unbranched chain C₂₋₄ alkylene. In someembodiments, X is an unbranched chain C₅₋₆ alkylene.

In some embodiments, R⁵ is —OH, C₁₋₄ alkoxy, —C₁₋₄ haloalkoxy, CO₂R^(a);or —NR^(b)R^(c).

In certain embodiments, R⁵ is —OH, C₁₋₄ alkoxy, —C₁₋₄ haloalkoxy, orCO₂R^(a).

In certain embodiments, R⁵ is C₁₋₄ alkoxy or —C₁₋₄ haloalkoxy (e.g.,C₁₋₄ alkoxy, e.g., OCH₃).

In certain embodiments, R⁵ is CO₂R^(a).

In some embodiments, R⁵ is H. In certain of these embodiments, R¹ isunsubstituted C₁₋₂ alkyl (e.g., CH₃).

In certain of these embodiments, R^(a) is C₁₋₆ alkyl optionallysubstituted with —OH, —NH₂, —NH(C₁₋₃ alkyl), —N(C₁₋₃ alkyl)₂,—N(H)(C(═O)C₁₋₃ alkyl), or cyano.

In certain of these embodiments, R^(a) is unsubstituted C₁₋₆ alkyl(e.g., CH₃ or CH₂CH₃).

In some embodiments, R¹ is:

(iii) (C₁₋₃ alkylene)-aryl, wherein the aryl is optionally substitutedwith from 1-3 R^(d); or

(iv) (C₁₋₃ alkylene)heteroaryl including from 5-6 ring atoms, whereinfrom 1-4 ring atoms are each independently selected from N, N(R^(f)), O,and S, and wherein the heteroaryl is optionally substituted with from1-3 R^(d).

In certain embodiments, R¹ is (C₁₋₃ alkylene)aryl, wherein the aryl isoptionally substituted with from 1-3 (e.g., 2, 1) R^(d).

In certain embodiments, R¹ is (C₁₋₃ alkylene)phenyl, wherein the phenylis optionally substituted with from 1-3 (e.g., 2, 1) R^(d).

In certain embodiments, R¹ is (C₁₋₃ alkylene)aryl, wherein the aryl issubstituted with from 1-3 (e.g., 2, 1) R^(d).

In certain embodiments, R¹ is (C₁₋₃ alkylene)phenyl, wherein the phenylis substituted with from 1-3 (e.g., 2, 1) R^(d).

In certain embodiments, R¹ is (C₁₋₃ alkylene)phenyl, wherein the phenylis substituted with 1 R^(d).

In certain of these embodiments, R^(d), or at least one R^(d) is C₁₋₆(e.g., C₁₋₄, C₁₋₃, C₁₋₂, C₁) alkyl optionally substituted with from 1-2substituents independently selected from —OH, C₁₋₄ alkoxy, C₁₋₄haloalkoxy, —C(═O)O(C₁₋₄ alkyl); —CON(R′)(R″), cyano, and —NR^(j)R^(k).

In certain of these embodiments, R^(d), or at least one R^(d) is C₁₋₆(e.g., C₁₋₄, C₁₋₃, C₁₋₂, C₁) alkyl substituted with from 1-2substituents independently selected from —OH, C₁₋₄ alkoxy, C₁₋₄haloalkoxy, —C(═O)O(C₁₋₄ alkyl); —CONR′R′, cyano, and —NR^(j)R^(k). Byway of example, R^(d) can be —CH₂NR^(j)R^(k), e.g., —CH₂NH₂.

Non-Limiting Combinations

[1] In some embodiments:

W′ is R²;

R² is Y—R⁶, wherein:

-   -   Y is C₁₋₈ alkylene, which is optionally substituted with from        1-4 R^(e); and    -   R⁶ is —OH, CO₂R^(a); —CONR′R″, —NR^(b)R^(c), or heteroaryl        including from 5-6 ring atoms, wherein from 1-4 ring atoms are        each independently selected from N, N(R^(f)), O, and S, wherein        the heteroaryl is optionally substituted with from 1-3 R^(d);        and

W is hydrogen.

In some of these embodiments, each of R³ and R is independently selectedfrom:

(i) H;

(ii) halo;

(iii) cyano;

(x) Y⁴—(C₁₋₃ alkylene)_(y)-C₅₋₈ cycloalkyl, wherein the cycloalkyl isoptionally substituted with from 1-4 independently selected R^(g)wherein y is 0 or 1; and Y⁴ is a bond, N(R^(f)), O, or S;

(xi) Y⁴—(C₁₋₃ alkylene)_(y)-heterocyclyl including from 5-8 ring atoms,wherein from 1-3 ring atoms are each independently selected fromN(R^(f)), O, and S, wherein the heterocyclyl is optionally substitutedwith from 1-4 independently selected R^(g), wherein y is 0 or 1; and Y⁴is a bond, N(R^(f)), O, or S;

(xii) Y⁴—(C₁₋₃ alkylene)_(y)-C₆₋₁₀ aryl optionally substituted with from1-4 R^(d), wherein y is 0 or 1; and Y⁴ is a bond, N(R^(f)), O, or S;

(xiii) Y⁴—(C₁₋₃ alkylene)_(y)-heteroaryl including from 5-10 ring atoms,wherein from 1-4 ring atoms are each independently selected from N,N(R^(f)), O, and S, wherein the heteroaryl is optionally substitutedwith from 1-3 R^(d), wherein y is 0 or 1; and Y⁴ is a bond, N(R^(f)), O,or S; and

(vii) C₁₋₄ haloalkyl.

In some embodiments, one of R³ and R⁴ (e.g., R³) is:

(ii) halo;

(iii) cyano;

(x) Y⁴—(C₁₋₃ alkylene)_(y)-C₅₋₈ cycloalkyl, wherein the cycloalkyl isoptionally substituted with from 1-4 independently selected R^(g)wherein y is 0 or 1; and Y⁴ is a bond, N(R^(f)), O, or S;

(xi) Y⁴—(C₁₋₃ alkylene)_(y)-heterocyclyl including from 5-8 ring atoms,wherein from 1-3 ring atoms are each independently selected fromN(R^(f)), O, and S, wherein the heterocyclyl is optionally substitutedwith from 1-4 independently selected R^(g), wherein y is 0 or 1; and Y⁴is a bond, N(R^(f)), O, or S;

(xii) Y⁴—(C₁₋₃ alkylene)_(y)-C₆₋₁₀ aryl optionally substituted with from1-4 R^(d), wherein y is 0 or 1; and Y⁴ is a bond, N(R^(f)), O, or S;

(xiii) Y⁴—(C₁₋₃ alkylene)_(y)-heteroaryl including from 5-10 ring atoms,wherein from 1-4 ring atoms are each independently selected from N,N(R^(f)), O, and S, wherein the heteroaryl is optionally substitutedwith from 1-3 R^(d), wherein y is 0 or 1; and Y⁴ is a bond, N(R^(f)), O,or S;

and

(vii) C₁₋₄ haloalkyl; and the other (e.g., R⁴) is H.

In some embodiments, one of R³ and R⁴ (e.g., R³) is —(C₁₋₃alkylene)_(y)-heteroaryl including from 5-10 ring atoms, wherein from1-4 ring atoms are each independently selected from N, N(R^(f)), O, andS, wherein the heteroaryl is optionally substituted with from 1-3 R^(d),wherein y is 0 or 1; and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is heteroarylincluding from 5-10 ring atoms, wherein from 1-4 ring atoms are eachindependently selected from N, N(R^(f)), O, and S, wherein theheteroaryl is optionally substituted with from 1-3 R^(d), wherein y is 0or 1; and the other (e.g., R⁴) is H.

Representative heteroaryl groups include, without limitation, thienyl,pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl,triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl,pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl,benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl,cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl,naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl,pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl,thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl,pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine,pyrazolo[4,3-b]pyridinyl, tetrazolyl, chromane,2,3-dihydrobenzo[b][1,4]dioxine, benzo[d][1,3]dioxole,2,3-dihydrobenzofuran, tetrahydroquinoline,2,3-dihydrobenzo[b][1,4]oxathiine, isoindoline.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is heteroarylincluding from 5-6 ring atoms, wherein from 1-4 ring atoms are eachindependently selected from N, N(R^(f)), O, and S, wherein theheteroaryl is optionally substituted with from 1-2 R^(d); and the other(e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is heteroarylincluding from 5-6 ring atoms, wherein from 1-4 ring atoms are eachindependently selected from N and N(R^(f)), wherein the heteroaryl isoptionally substituted with from 1-2 R^(d); and the other (e.g., R⁴) isH.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is pyrrolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, orpyrazinyl, wherein each is optionally substituted with from 1-2 R^(d);and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is pyrrolyl,imidazolyl, pyrazolyl, triazolyl, or tetrazolyl, wherein each isoptionally substituted with from 1-2 R^(d); and the other (e.g., R⁴) isH.

In certain embodiments, one of R³ and R⁴ (e.g., R³) isN-linked-pyrazolyl, N-linked pyrrolyl, N-linked imidazolyl, N-linkedtriazolyl, or N-linked tetrazolyl, optionally substituted with from 1-2R^(d); and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) isC-linked-pyrazolyl, C-linked pyrrolyl, C-linked imidazolyl, C-linkedtriazolyl, or C-linked tetrazolyl, optionally substituted with from 1-2R^(d); and the other (e.g., R⁴) is H. In certain embodiments, one of R³and R⁴ (e.g., R³) is pyrazolyl, optionally substituted with from 1-2R^(d); and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is C-linkedpyrazolyl, optionally substituted with from 1-2 R^(d); and the other(e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is N-linkedpyrazolyl, optionally substituted with from 1-2 R^(d); and the other(e.g., R⁴) is H.

In some embodiments, one of R³ and R⁴ (e.g., R³) is —(C₁₋₃alkylene)_(y)-C₆₋₁₀ aryl, wherein the aryl is optionally substitutedwith from 1-3 R^(d), wherein y is 0 or 1; and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is C₆₋₁₀ aryl (e.g.,phenyl), optionally substituted with from 1-3 R^(d), wherein y is 0 or1; and the other (e.g., R⁴) is H.

In some embodiments, one of R³ and R⁴ (e.g., R³) is —(C₁₋₃alkylene)_(y)-heterocyclyl including from 3-10 ring atoms, wherein from1-3 ring atoms are each independently selected from N(R^(f)), O, and S,wherein the heterocyclyl is optionally substituted with from 1-4independently selected R^(g), wherein y is 0 or 1; and the other (e.g.,R⁴) is H.

In some embodiments, one of R³ and R⁴ (e.g., R³) is heterocyclylincluding from 3-10 ring atoms, wherein from 1-3 ring atoms are eachindependently selected from N(R^(f)), O, and S, wherein the heterocyclylis optionally substituted with from 1-4 independently selected R^(g)(e.g., oxo), and the other (e.g., R⁴) is H.

[2] In some embodiments:

W is R²;

R² is Y—R⁶, wherein:

-   -   Y is C₁₋₈ alkylene, which is optionally substituted with from        1-4 R^(e); and    -   R⁶ is —OH, CO₂R^(a); —CONR′R″, —NR^(b)R^(c), or heteroaryl        including from 5-6 ring atoms, wherein from 1-4 ring atoms are        each independently selected from N, N(R^(f)), O, and S; and

W′ is H.

In some embodiments, each of R³ and R⁴ is independently selected from:

(i) H;

(ii) halo;

(iii) cyano;

(x) Y⁴—(C₁₋₃ alkylene)_(y)-C₅₋₈ cycloalkyl, wherein the cycloalkyl isoptionally substituted with from 1-4 independently selected R^(g),wherein y is 0 or 1; and Y⁴ is a bond, N(R^(f)), O, or S;

(xi) Y⁴—(C₁₋₃ alkylene)_(y)-heterocyclyl including from 5-8 ring atoms,wherein from 1-3 ring atoms are each independently selected fromN(R^(f)), O, and S, wherein the heterocyclyl is optionally substitutedwith from 1-4 independently selected R^(g), wherein y is 0 or 1; and Y⁴is a bond, N(R^(f)), O, or S;

(xii) Y⁴—(C₁₋₃ alkylene)_(y)-C₆₋₁₀ aryl optionally substituted with from1-4 R^(d), wherein y is 0 or 1; and Y⁴ is a bond, N(R^(f)), O, or S;

(xiii) Y⁴—(C₁₋₃ alkylene)_(y)-heteroaryl including from 5-10 ring atoms,wherein from 1-4 ring atoms are each independently selected from N,N(R^(f)), O, and S, wherein the heteroaryl is optionally substitutedwith from 1-3 R^(d), wherein y is 0 or 1; and Y⁴ is a bond, N(R^(f)), O,or S;

and

(vii) C₁₋₄ haloalkyl.

In some embodiments, one of R³ and R⁴ (e.g., R³) is:

(ii) halo;

(iii) cyano;

(x) Y⁴—(C₁₋₃ alkylene)_(y)-C₅₋₈ cycloalkyl, wherein the cycloalkyl isoptionally substituted with from 1-4 independently selected R^(g)wherein y is 0 or 1; and Y⁴ is a bond, N(R^(f)), O, or S;

(xi) Y⁴—(C₁₋₃ alkylene)_(y)-heterocyclyl including from 5-8 ring atoms,wherein from 1-3 ring atoms are each independently selected fromN(R^(f)), O, and S, wherein the heterocyclyl is optionally substitutedwith from 1-4 independently selected R^(g), wherein y is 0 or 1; and Y⁴is a bond, N(R^(f)), O, or S;

(xii) Y⁴—(C₁₋₃ alkylene)_(y)-C₆₋₁₀ aryl optionally substituted with from1-4 R^(d), wherein y is 0 or 1; and Y⁴ is a bond, N(R^(f)), O, or S;

(xiii) Y⁴—(C₁₋₃ alkylene)_(y)-heteroaryl including from 5-10 ring atoms,wherein from 1-4 ring atoms are each independently selected from N,N(R^(f)), O, and S, wherein the heteroaryl is optionally substitutedwith from 1-3 R^(d), wherein y is 0 or 1; and Y⁴ is a bond, N(R^(f)), O,or S;

and

(vii) C₁₋₄ haloalkyl; and the other (e.g., R⁴) is H.

In some embodiments, one of R³ and R⁴ (e.g., R³) is —(C₁₋₃alkylene)_(y)-heteroaryl including from 5-10 ring atoms, wherein from1-4 ring atoms are each independently selected from N, N(R^(f)), O, andS, wherein the heteroaryl is optionally substituted with from 1-3 R^(d),wherein y is 0 or 1; and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is heteroarylincluding from 5-10 ring atoms, wherein from 1-4 ring atoms are eachindependently selected from N, N(R^(f)), O, and S, wherein theheteroaryl is optionally substituted with from 1-3 R^(d); and the other(e.g., R⁴) is H.

Representative heteroaryl groups include, without limitation, thienyl,pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl,triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl,pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl,benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl,cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl,naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl,pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl,thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl,pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine,pyrazolo[4,3-b]pyridinyl, tetrazolyl, chromane,2,3-dihydrobenzo[b][1,4]dioxine, benzo[d][1,3]dioxole,2,3-dihydrobenzofuran, tetrahydroquinoline,2,3-dihydrobenzo[b][1,4]oxathiine, isoindoline.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is heteroarylincluding from 5-6 ring atoms, wherein from 1-4 ring atoms are eachindependently selected from N, N(R^(f)), O, and S, wherein theheteroaryl is optionally substituted with from 1-2 R^(d); and the other(e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is heteroarylincluding from 5-6 ring atoms, wherein from 1-4 ring atoms are eachindependently selected from N and N(R^(f)), wherein the heteroaryl isoptionally substituted with from 1-2 R^(d); and the other (e.g., R⁴) isH.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is pyrrolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, orpyrazinyl, wherein each is optionally substituted with from 1-2 R^(d);and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is pyrrolyl,imidazolyl, pyrazolyl, triazolyl, or tetrazolyl, wherein each isoptionally substituted with from 1-2 R^(d); and the other (e.g., R⁴) isH.

In certain embodiments, one of R³ and R⁴ (e.g., R³) isN-linked-pyrazolyl, N-linked pyrrolyl, N-linked imidazolyl, N-linkedtriazolyl, or N-linked tetrazolyl, optionally substituted with from 1-2R^(d); and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) isC-linked-pyrazolyl, C-linked pyrrolyl, C-linked imidazolyl, C-linkedtriazolyl, or C-linked tetrazolyl, optionally substituted with from 1-2R^(d); and the other (e.g., R⁴) is H. In certain embodiments, one of R³and R⁴ (e.g., R³) is pyrazolyl, optionally substituted with from 1-2R^(d); and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is C-linkedpyrazolyl, optionally substituted with from 1-2 R^(d); and the other(e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is N-linkedpyrazolyl, optionally substituted with from 1-2 R^(d); and the other(e.g., R⁴) is H.

In some embodiments, one of R³ and R⁴ (e.g., R³) is —(C₁₋₃alkylene)_(y)-C₆₋₁₀ aryl, wherein the aryl is optionally substitutedwith from 1-3 R^(d), wherein y is 0 or 1; and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is C₆₋₁₀ aryl (e.g.,phenyl), optionally substituted with from 1-3 R^(d); and the other(e.g., R⁴) is H.

In some embodiments, one of R³ and R⁴ (e.g., R³) is —(C₁₋₃alkylene)_(y)-heterocyclyl including from 3-10 ring atoms, wherein from1-3 ring atoms are each independently selected from N(R^(f)), O, and S,wherein the heterocyclyl is optionally substituted with from 1-4independently selected R^(g), wherein y is 0 or 1; and the other (e.g.,R⁴) is H.

In some embodiments, one of R³ and R⁴ (e.g., R³) is heterocyclylincluding from 3-10 ring atoms, wherein from 1-3 ring atoms are eachindependently selected from N(R^(f)), O, and S, wherein the heterocyclylis optionally substituted with from 1-4 independently selected R^(g)(e.g., oxo), and the other (e.g., R⁴) is H.

[3] In some embodiments:

W′ is R²;

R² is —(Y¹)_(n)—Y²—(Y³)_(p)—R^(6′), wherein:

-   -   each of n and p is independently 0 or 1;    -   each of Y¹ and Y³ is, independently, C₁₋₃ alkylene, which is        optionally substituted with from 1-2 R^(e),    -   Y² is C₃₋₆ cycloalkylene or heterocycloalkylene including from        3-8 ring atoms, wherein from 1-2 ring atoms are each        independently selected from N, N(R^(f)) and O, and wherein Y² is        optionally further substituted with from 1-4 R^(g), and    -   R^(6′) is —OH, CO₂R^(a); —CONR′R″, —NR^(b)R^(c), or heteroaryl        including from 5-6 ring atoms, wherein from 1-4 ring atoms are        each independently selected from N, N(R^(f)), O, and S;

and W is hydrogen.

[4] In some embodiments:

W is R²;

R² is —(Y¹)_(n)—Y²—(Y³)_(p)—R^(6′), wherein:

-   -   each of n and p is independently 0 or 1;    -   each of Y¹ and Y³ is, independently, C₁₋₃ alkylene, which is        optionally substituted with from 1-2 R^(e),    -   Y² is C₃₋₆ cycloalkylene or heterocycloalkylene including from        3-8 ring atoms, wherein from 1-2 ring atoms are each        independently selected from N, N(R^(f)) and oxygen, and wherein        Y² is optionally further substituted with from 1-4 R^(g), and    -   R^(6′) is H, —OH, CO₂R^(a); —CONR′R″, —NR^(b)R^(c), or        heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring        atoms are each independently selected from N, N(R^(f)), O, and        S, wherein R^(6′) cannot be H when Y² is C₃₋₆ cycloalkylene        optionally substituted with from 1-4 R^(g);

and W′ is hydrogen.

In some embodiments of combination [3] and [4], each of R³ and R⁴ isindependently selected from:

(i) H;

(ii) halo;

(iii) cyano;

(x) Y⁴—(C₁₋₃ alkylene)_(y)-C₅₋₈ cycloalkyl, wherein the cycloalkyl isoptionally substituted with from 1-4 independently selected R^(g)wherein y is 0 or 1; and Y⁴ is a bond, N(R^(f)), O, or S;

(xi) Y⁴—(C₁₋₃ alkylene)_(y)-heterocyclyl including from 5-8 ring atoms,wherein from 1-3 ring atoms are each independently selected fromN(R^(f)), O, and S, wherein the heterocyclyl is optionally substitutedwith from 1-4 independently selected R^(g), wherein y is 0 or 1; and Y⁴is a bond, N(R^(f)), O, or S;

(xii) Y⁴—(C₁₋₃ alkylene)_(y)-C₆₋₁₀ aryl optionally substituted with from1-4 R^(d), wherein y is 0 or 1; and Y⁴ is a bond, N(R^(f)), O, or S;

(xiii) Y⁴—(C₁₋₃ alkylene)_(y)-heteroaryl including from 5-10 ring atoms,wherein from 1-4 ring atoms are each independently selected from N,N(R^(f)), O, and S, wherein the heteroaryl is optionally substitutedwith from 1-3 R^(d), wherein y is 0 or 1; and Y⁴ is a bond, N(R^(f)), O,or S;

and

(vii) C₁₋₄ haloalkyl.

In some embodiments, one of R³ and R⁴ (e.g., R³) is:

(ii) halo;

(iii) cyano;

(x) Y⁴—(C₁₋₃ alkylene)_(y)-C₅₋₈ cycloalkyl, wherein the cycloalkyl isoptionally substituted with from 1-4 independently selected R^(g)wherein y is 0 or 1; and Y⁴ is a bond, N(R^(f)), O, or S;

(xi) Y⁴—(C₁₋₃ alkylene)_(y)-heterocyclyl including from 5-8 ring atoms,wherein from 1-3 ring atoms are each independently selected fromN(R^(f)), O, and S, wherein the heterocyclyl is optionally substitutedwith from 1-4 independently selected R^(g), wherein y is 0 or 1; and Y⁴is a bond, N(R^(f)), O, or S;

(xii) Y⁴—(C₁₋₃ alkylene)_(y)-C₆₋₁₀ aryl optionally substituted with from1-4 R^(d), wherein y is 0 or 1; and Y⁴ is a bond, N(R^(f)), O, or S;

(xiii) Y⁴—(C₁₋₃ alkylene)_(y)-heteroaryl including from 5-10 ring atoms,wherein from 1-4 ring atoms are each independently selected from N,N(R^(f)), O, and S, wherein the heteroaryl is optionally substitutedwith from 1-3 R^(d), wherein y is 0 or 1; and Y⁴ is a bond, N(R^(f)), O,or S;

and

(vii) C₁₋₄ haloalkyl; and the other (e.g., R⁴) is H.

In some embodiments, one of R³ and R⁴ (e.g., R³) is —(C₁₋₃alkylene)_(y)-heteroaryl including from 5-10 ring atoms, wherein from1-4 ring atoms are each independently selected from N, N(R^(f)), O, andS, wherein the heteroaryl is optionally substituted with from 1-3 R^(d),wherein y is 0 or 1; and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is heteroarylincluding from 5-10 ring atoms, wherein from 1-4 ring atoms are eachindependently selected from N, N(R^(f)), O, and S, wherein theheteroaryl is optionally substituted with from 1-3 R^(d); and the other(e.g., R⁴) is H.

Representative heteroaryl groups include, without limitation, thienyl,pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl,triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl,pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl,benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl,cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl,naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl,pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl,thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl,pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine,pyrazolo[4,3-b]pyridinyl, tetrazolyl, chromane,2,3-dihydrobenzo[b][1,4]dioxine, benzo[d][1,3]dioxole,2,3-dihydrobenzofuran, tetrahydroquinoline,2,3-dihydrobenzo[b][1,4]oxathiine, isoindoline.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is heteroarylincluding from 5-6 ring atoms, wherein from 1-4 ring atoms are eachindependently selected from N, N(R^(f)), O, and S, wherein theheteroaryl is optionally substituted with from 1-2 R^(d); and the other(e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is heteroarylincluding from 5-6 ring atoms, wherein from 1-4 ring atoms are eachindependently selected from N and N(R^(f)), wherein the heteroaryl isoptionally substituted with from 1-2 R^(d); and the other (e.g., R⁴) isH.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is heteroarylincluding 5 ring atoms, wherein from 1 ring atom is independentlyselected from O and S (e.g., S), wherein the heteroaryl is optionallysubstituted with from 1-2 R^(d); and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is pyrrolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, orpyrazinyl, wherein each is optionally substituted with from 1-2 R^(d);and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is pyrrolyl,imidazolyl, pyrazolyl, triazolyl, or tetrazolyl, wherein each isoptionally substituted with from 1-2 R^(d); and the other (e.g., R⁴) isH.

In certain embodiments, one of R³ and R⁴ (e.g., R³) isN-linked-pyrazolyl, N-linked pyrrolyl, N-linked imidazolyl, N-linkedtriazolyl, or N-linked tetrazolyl, optionally substituted with from 1-2R^(d); and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) isC-linked-pyrazolyl, C-linked pyrrolyl, C-linked imidazolyl, C-linkedtriazolyl, or C-linked tetrazolyl, optionally substituted with from 1-2R^(d); and the other (e.g., R⁴) is H. In certain embodiments, one of R³and R⁴ (e.g., R³) is pyrazolyl, optionally substituted with from 1-2R^(d); and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is C-linkedpyrazolyl, optionally substituted with from 1-2 R^(d); and the other(e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is N-linkedpyrazolyl, optionally substituted with from 1-2 R^(d); and the other(e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is furyl or thienyl,optionally substituted with from 1-2 R^(d); and the other (e.g., R⁴) isH.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is thienyl,optionally substituted with from 1-2 R^(d); and the other (e.g., R⁴) isH.

In some embodiments, one of R³ and R⁴ (e.g., R³) is —(C₁₋₃alkylene)_(y)-C₆₋₁₀ aryl, wherein the aryl is optionally substitutedwith from 1-3 R^(d), wherein y is 0 or 1; and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is C₆₋₁₀ aryl (e.g.,phenyl), optionally substituted with from 1-3 R^(d); and the other(e.g., R⁴) is H.

In some embodiments, one of R³ and R⁴ (e.g., R³) is —(C₁₋₃alkylene)_(y)-heterocyclyl including from 3-10 ring atoms, wherein from1-3 ring atoms are each independently selected from N(R^(f)), O, and S,wherein the heterocyclyl is optionally substituted with from 1-4independently selected R^(g), wherein y is 0 or 1; and the other (e.g.,R⁴) is H.

In some embodiments, one of R³ and R⁴ (e.g., R³) is heterocyclylincluding from 3-10 ring atoms, wherein from 1-3 ring atoms are eachindependently selected from N(R¹), O, and S, wherein the heterocyclyl isoptionally substituted with from 1-4 independently selected R^(g) (e.g.,oxo), and the other (e.g., R⁴) is H.

[5] In some embodiments:

W′ is R²;

R² has formula (R²-A)

wherein:

R⁸ and R⁹, are defined according to (1) or (2) below:

(1):

R⁸ is independently selected from: H; C₁₋₈ (e.g., C₁₋₆) alkyl optionallysubstituted with from 1-2 independently selected R^(e); —C(O)(R^(a));—C(O)O(R^(a)); —S(O)₁₋₂(R^(h)); —C(O)NR′R″; and —S(O)₁₋₂(NR′R″);

R⁹ is independently selected from: H and C₁₋₆ alkyl optionallysubstituted with from 1-2 independently selected R^(e); and

OR

(2):

R⁸ and R⁹, together with the nitrogen atom to which each is attachedforms a saturated ring including from 3-10 ring atoms, wherein the ringincludes:

(a) from 1-9 ring carbon atoms, each of which is substituted with from1-2 substituents independently selected from H and R^(g), and

(b) from 0-3 ring heteroatoms (in addition to the nitrogen atom attachedto R⁸ and R⁹), each of which is independently selected from N, N(R^(f)),O, and S; and

each of R¹⁰ and R¹¹ is independently selected from: H and unsubstitutedC₁₋₂ alkyl; or R¹⁰ and R¹¹ together with the carbon atom to which eachis attached, forms a C₃-C₅ cycloalkyl, optionally substituted with from1-4 independently selected R^(g);

and W is hydrogen.

[6] In some embodiments:

W is R²;

R² has formula (R²-A)

wherein:

R⁸ and R⁹, are defined according to (1) or (2) below:

(1):

R⁸ is independently selected from: H; C₁₋₈ (e.g., C₁₋₆) alkyl optionallysubstituted with from 1-2 independently selected R; —C(O)(R^(a));—C(O)O(R^(a)); —S(O)₁₋₂(R^(h)); —C(O)NR′R″; and —S(O)₁₋₂(NR′R″);

R⁹ is independently selected from: H and C₁₋₆ alkyl optionallysubstituted with from 1-2 independently selected R^(e); and

OR

(2):

R⁸ and R⁹, together with the nitrogen atom to which each is attachedforms a saturated ring including from 3-10 ring atoms, wherein the ringincludes:

(a) from 1-9 ring carbon atoms, each of which is substituted with from1-2 substituents independently selected from H and R^(g), and

(b) from 0-3 ring heteroatoms (in addition to the nitrogen atom attachedto R⁸ and R⁹), each of which is independently selected from N, N(R^(f)),O, and S; and

each of R¹⁰ and R¹¹ is independently selected from: H and unsubstitutedC₁₋₂ alkyl; or R¹⁰ and R¹¹ together with the carbon atom to which eachis attached, forms a C₃-C₅ cycloalkyl, optionally substituted with from1-4 independently selected R^(g);

and W′ is hydrogen.

In some embodiments of combination [5] and [6], each of R³ and R⁴ isindependently selected from:

(i) H;

(ii) halo;

(iii) cyano;

(x) Y⁴—(C₁₋₃ alkylene)_(y)-C₅₋₈ cycloalkyl, wherein the cycloalkyl isoptionally substituted with from 1-4 independently selected R^(g),wherein y is 0 or 1; and Y⁴ is a bond, N(R^(f)), O, or S;

(xi) Y⁴—(C₁₋₃ alkylene)_(y)-heterocyclyl including from 5-8 ring atoms,wherein from 1-3 ring atoms are each independently selected fromN(R^(f)), O, and S, wherein the heterocyclyl is optionally substitutedwith from 1-4 independently selected R^(g), wherein y is 0 or 1; and Y⁴is a bond, N(R^(f)), O, or S;

(xii) Y⁴—(C₁₋₃ alkylene)_(y)-C₆₋₁₀ aryl optionally substituted with from1-4 R^(d), wherein y is 0 or 1; and Y⁴ is a bond, N(R^(f)), O, or S;

(xiii) Y⁴—(C₁₋₃ alkylene)_(y)-heteroaryl including from 5-10 ring atoms,wherein from 1-4 ring atoms are each independently selected from N,N(R^(f)), O, and S, wherein the heteroaryl is optionally substitutedwith from 1-3 R^(d), wherein y is 0 or 1; and Y⁴ is a bond, N(R^(f)), O,or S;

and

(vii) C₁₋₄ haloalkyl.

In some embodiments, one of R³ and R⁴ (e.g., R³) is:

(ii) halo;

(iii) cyano;

(x) Y⁴—(C₁₋₃ alkylene)_(y)-C₅₋₈ cycloalkyl, wherein the cycloalkyl isoptionally substituted with from 1-4 independently selected R^(g)wherein y is 0 or 1; and Y⁴ is a bond, N(R^(f)), O, or S;

(xi) Y⁴—(C₁₋₃ alkylene)_(y)-heterocyclyl including from 5-8 ring atoms,wherein from 1-3 ring atoms are each independently selected fromN(R^(f)), O, and S, wherein the heterocyclyl is optionally substitutedwith from 1-4 independently selected R^(g), wherein y is 0 or 1; and Y⁴is a bond, N(R^(f)), O, or S;

(xii) Y⁴—(C₁₋₃ alkylene)_(y)-C₆₋₁₀ aryl optionally substituted with from1-4 R^(d), wherein y is 0 or 1; and Y⁴ is a bond, N(R^(f)), O, or S;

(xiii) Y⁴—(C₁₋₃ alkylene)_(y)-heteroaryl including from 5-10 ring atoms,wherein from 1-4 ring atoms are each independently selected from N,N(R^(f)), O, and S, wherein the heteroaryl is optionally substitutedwith from 1-3 R^(d), wherein y is 0 or 1; and Y⁴ is a bond, N(R^(f)), O,or S;

and

(vii) C₁₋₄ haloalkyl; and the other (e.g., R⁴) is H.

In some embodiments, one of R³ and R⁴ (e.g., R³) is —(C₁₋₃alkylene)_(y)-heteroaryl including from 5-10 ring atoms, wherein from1-4 ring atoms are each independently selected from N, N(R^(f)), O, andS, wherein the heteroaryl is optionally substituted with from 1-3 R^(d),wherein y is 0 or 1; and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is heteroarylincluding from 5-10 ring atoms, wherein from 1-4 ring atoms are eachindependently selected from N, N(R^(f)), O, and S, wherein theheteroaryl is optionally substituted with from 1-3 R; and the other(e.g., R⁴) is H.

Representative heteroaryl groups include, without limitation, thienyl,pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl,triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl,pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl,benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl,cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl,naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl,pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl,thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl,pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine,pyrazolo[4,3-b]pyridinyl, tetrazolyl, chromane,2,3-dihydrobenzo[b][1,4]dioxine, benzo[d][1,3]dioxole,2,3-dihydrobenzofuran, tetrahydroquinoline,2,3-dihydrobenzo[b][1,4]oxathiine, isoindoline.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is heteroarylincluding from 5-6 ring atoms, wherein from 1-4 ring atoms are eachindependently selected from N, N(R^(f)), O, and S, wherein theheteroaryl is optionally substituted with from 1-2 R^(d); and the other(e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is heteroarylincluding from 5-6 ring atoms, wherein from 1-4 ring atoms are eachindependently selected from N and N(R^(f)), wherein the heteroaryl isoptionally substituted with from 1-2 R^(d); and the other (e.g., R⁴) isH.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is heteroarylincluding 5 ring atoms, wherein from 1 ring atom is independentlyselected from O and S (e.g., S), wherein the heteroaryl is optionallysubstituted with from 1-2 R^(d); and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is pyrrolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, orpyrazinyl, wherein each is optionally substituted with from 1-2 R^(d);and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is pyrrolyl,imidazolyl, pyrazolyl, triazolyl, or tetrazolyl, wherein each isoptionally substituted with from 1-2 R^(d); and the other (e.g., R⁴) isH.

In certain embodiments, one of R³ and R⁴ (e.g., R³) isN-linked-pyrazolyl, N-linked pyrrolyl, N-linked imidazolyl, N-linkedtriazolyl, or N-linked tetrazolyl, optionally substituted with from 1-2R^(d); and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) isC-linked-pyrazolyl, C-linked pyrrolyl, C-linked imidazolyl, C-linkedtriazolyl, or C-linked tetrazolyl, optionally substituted with from 1-2R^(d); and the other (e.g., R⁴) is H. In certain embodiments, one of R³and R⁴ (e.g., R³) is pyrazolyl, optionally substituted with from 1-2R^(d); and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is C-linkedpyrazolyl, optionally substituted with from 1-2 R^(d); and the other(e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is N-linkedpyrazolyl, optionally substituted with from 1-2 R^(d); and the other(e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is furyl or thienyl,optionally substituted with from 1-2 R^(d); and the other (e.g., R⁴) isH.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is thienyl,optionally substituted with from 1-2 R^(d); and the other (e.g., R⁴) isH.

In some embodiments, one of R³ and R⁴ (e.g., R³) is —(C₁₋₃alkylene)_(y)-C₆₋₁₀ aryl, wherein the aryl is optionally substitutedwith from 1-3 R^(d), wherein y is 0 or 1; and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is C₆₋₁₀ aryl (e.g.,phenyl), optionally substituted with from 1-3 R^(d); and the other(e.g., R⁴) is H.

In some embodiments, one of R³ and R⁴ (e.g., R³) is —(C₁₋₃alkylene)_(y)-heterocyclyl including from 3-10 ring atoms, wherein from1-3 ring atoms are each independently selected from N(R^(f)), O, and S,wherein the heterocyclyl is optionally substituted with from 1-4independently selected R^(g), wherein y is 0 or 1; and the other (e.g.,R⁴) is H.

In some embodiments, one of R³ and R⁴ (e.g., R³) is heterocyclylincluding from 3-10 ring atoms, wherein from 1-3 ring atoms are eachindependently selected from N(R^(f)), O, and S, wherein the heterocyclylis optionally substituted with from 1-4 independently selected R^(g)(e.g., oxo), and the other (e.g., R⁴) is H.

[7] In some embodiments:

In some embodiments, one of W and W′ is R², and the other is H;

In some embodiments, R² is

wherein:

R⁶ is independently selected from: —OH, —O(C₁₋₄ alkyl), —CO₂R^(a),—C(O)NR′R′; and heteroaryl including from 5-6 ring atoms, wherein from1-3 ring atoms are each independently selected from N, N(R^(f)), O, andS, wherein the heteroaryl is optionally substituted with from 1-3 R^(d).

In some embodiments of combination [7], each of R³ and R⁴ isindependently selected from:

(i) H;

(ii) halo;

(iii) cyano;

(x) Y⁴—(C₁₋₃ alkylene)_(y)-C₅₋₈ cycloalkyl, wherein the cycloalkyl isoptionally substituted with from 1-4 independently selected R^(g),wherein y is 0 or 1; and Y⁴ is a bond, N(R^(f)), O, or S;

(xi) Y⁴—(C₁₋₃ alkylene)_(y)-heterocyclyl including from 5-8 ring atoms,wherein from 1-3 ring atoms are each independently selected fromN(R^(f)), O, and S, wherein the heterocyclyl is optionally substitutedwith from 1-4 independently selected R^(g), wherein y is 0 or 1; and Y⁴is a bond, N(R^(f)), O, or S;

(xii) Y⁴—(C₁₋₃ alkylene)_(y)-C₆₋₁₀ aryl optionally substituted with from1-4 R^(d), wherein y is 0 or 1; and Y⁴ is a bond, N(R^(f)), O, or S;

(xiii) Y⁴—(C₁₋₃ alkylene)_(y)-heteroaryl including from 5-10 ring atoms,wherein from 1-4 ring atoms are each independently selected from N,N(R^(f)), O, and S, wherein the heteroaryl is optionally substitutedwith from 1-3 R^(d), wherein y is 0 or 1; and Y⁴ is a bond, N(R^(f)), O,or S;

and

(vii) C₁₋₄ haloalkyl.

In some embodiments, one of R³ and R⁴ (e.g., R³) is:

(ii) halo;

(iii) cyano;

(x) Y⁴—(C₁₋₃ alkylene)_(y)-C₅₋₈ cycloalkyl, wherein the cycloalkyl isoptionally substituted with from 1-4 independently selected R^(g)wherein y is 0 or 1; and Y⁴ is a bond, N(R^(f)), O, or S;

(xi) Y⁴—(C₁₋₃ alkylene)_(y)-heterocyclyl including from 5-8 ring atoms,wherein from 1-3 ring atoms are each independently selected fromN(R^(f)), O, and S, wherein the heterocyclyl is optionally substitutedwith from 1-4 independently selected R^(g), wherein y is 0 or 1; and Y⁴is a bond, N(R^(f)), O, or S;

(xii) Y⁴—(C₁₋₃ alkylene)_(y)-C₆₋₁₀ aryl optionally substituted with from1-4 R^(d), wherein y is 0 or 1; and Y⁴ is a bond, N(R^(f)), O, or S;

(xiii) Y⁴—(C₁₋₃ alkylene)_(y)-heteroaryl including from 5-10 ring atoms,wherein from 1-4 ring atoms are each independently selected from N,N(R^(f)), O, and S, wherein the heteroaryl is optionally substitutedwith from 1-3 R^(d), wherein y is 0 or 1; and Y⁴ is a bond, N(R^(f)), O,or S;

and

(vii) C₁₋₄ haloalkyl; and the other (e.g., R⁴) is H.

In some embodiments, one of R³ and R⁴ (e.g., R³) is —(C₁₋₃alkylene)_(y)-heteroaryl including from 5-10 ring atoms, wherein from1-4 ring atoms are each independently selected from N, N(R^(f)), O, andS, wherein the heteroaryl is optionally substituted with from 1-3 R^(d),wherein y is 0 or 1; and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is heteroarylincluding from 5-10 ring atoms, wherein from 1-4 ring atoms are eachindependently selected from N, N(R^(f)), O, and S, wherein theheteroaryl is optionally substituted with from 1-3 R^(d); and the other(e.g., R⁴) is H.

Representative heteroaryl groups include, without limitation, thienyl,pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl,triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl,pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl,benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl,cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl,naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3-d]pyrimidinyl,pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl,thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl,pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine,pyrazolo[4,3-b]pyridinyl, tetrazolyl, chromane,2,3-dihydrobenzo[b][1,4]dioxine, benzo[d][1,3]dioxole,2,3-dihydrobenzofuran, tetrahydroquinoline,2,3-dihydrobenzo[b][1,4]oxathiine, isoindoline.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is heteroarylincluding from 5-6 ring atoms, wherein from 1-4 ring atoms are eachindependently selected from N, N(R^(f)), O, and S, wherein theheteroaryl is optionally substituted with from 1-2 R^(d); and the other(e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is heteroarylincluding from 5-6 ring atoms, wherein from 1-4 ring atoms are eachindependently selected from N and N(R^(f)), wherein the heteroaryl isoptionally substituted with from 1-2 R^(d); and the other (e.g., R⁴) isH.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is heteroarylincluding 5 ring atoms, wherein from 1 ring atom is independentlyselected from O and S (e.g., S), wherein the heteroaryl is optionallysubstituted with from 1-2 R^(d); and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is pyrrolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, orpyrazinyl, wherein each is optionally substituted with from 1-2 R^(d);and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is pyrrolyl,imidazolyl, pyrazolyl, triazolyl, or tetrazolyl, wherein each isoptionally substituted with from 1-2 R^(d); and the other (e.g., R⁴) isH.

In certain embodiments, one of R³ and R⁴ (e.g., R³) isN-linked-pyrazolyl, N-linked pyrrolyl, N-linked imidazolyl, N-linkedtriazolyl, or N-linked tetrazolyl, optionally substituted with from 1-2R^(d); and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) isC-linked-pyrazolyl, C-linked pyrrolyl, C-linked imidazolyl, C-linkedtriazolyl, or C-linked tetrazolyl, optionally substituted with from 1-2R^(d); and the other (e.g., R⁴) is H. In certain embodiments, one of R³and R⁴ (e.g., R³) is pyrazolyl, optionally substituted with from 1-2R^(d); and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is C-linkedpyrazolyl, optionally substituted with from 1-2 R^(d); and the other(e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is N-linkedpyrazolyl, optionally substituted with from 1-2 R^(d); and the other(e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is furyl or thienyl,optionally substituted with from 1-2 R^(d); and the other (e.g., R⁴) isH.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is thienyl,optionally substituted with from 1-2 R^(d); and the other (e.g., R⁴) isH.

In some embodiments, one of R³ and R⁴ (e.g., R³) is —(C₁₋₃alkylene)_(y)-C₆₋₁₀ aryl, wherein the aryl is optionally substitutedwith from 1-3 R^(d), wherein y is 0 or 1; and the other (e.g., R⁴) is H.

In certain embodiments, one of R³ and R⁴ (e.g., R³) is C₆₋₁₀ aryl (e.g.,phenyl), optionally substituted with from 1-3 R^(d); and the other(e.g., R⁴) is H.

In some embodiments, one of R³ and R⁴ (e.g., R³) is —(C₁₋₃alkylene)_(y)-heterocyclyl including from 3-10 ring atoms, wherein from1-3 ring atoms are each independently selected from N(R^(f)), O, and S,wherein the heterocyclyl is optionally substituted with from 1-4independently selected R^(g), wherein y is 0 or 1; and the other (e.g.,R⁴) is H.

In some embodiments, one of R³ and R⁴ (e.g., R³) is heterocyclylincluding from 3-10 ring atoms, wherein from 1-3 ring atoms are eachindependently selected from N(R^(f)), O, and S, wherein the heterocyclylis optionally substituted with from 1-4 independently selected R^(g)(e.g., oxo), and the other (e.g., R⁴) is H.

Embodiments of any one of combinations [1]-[11] can include one or moreof the following features.

Y can be C₁₋₆ (e.g., C₂₋₄, C₂₋₃, C₂) alkylene, which is optionallysubstituted with from 1-4 (e.g., 1-2, 1) R^(e). In certain embodiments,Y is C₂₋₆ (e.g., C₂₋₄, C₂₋₃, C₂) alkylene, which is unsubstituted (e.g.,C₂ alkylene or C₃ alkylene; e.g., C₃ alkylene).

R⁶ can be —OH, CO₂R^(a); -or —NR^(b)R^(c). For example, R⁶ can be —NH₂,—N(H)(C₁₋₄ alkyl) (e.g., —NHCH₃) or —N(C₁₋₄ alkyl)₂ (e.g., —N(CH₃)₂).R⁶can be —NR^(b)R^(c).

Each occurrence of R^(b) and R^(c) can be independently selected from:H, C₁₋₄ alkyl, —C(O)(C₁₋₄ alkyl), —C(O)O(C₁₋₄ alkyl), —S(O)₁₋₂(R^(h)),—C(O)NR′R′, —OH, and C₁₋₄ alkoxy.

Each occurrence of R^(b) and R^(c) can be independently selected from:H, C₁₋₄ alkyl, —C(O)(C₁₋₄ alkyl), —C(O)O(C₁₋₄ alkyl), —S(O)₁₋₂(R^(h)),and —C(O)NR′R′.

Each occurrence of R^(b) and R^(c) can be independently selected from:H, C₁₋₄ alkyl, and —C(O)(C₁₋₄ alkyl).

Each occurrence of R^(b) and R^(c) can be independently selected from: Hand C₁₋₄ alkyl.

Each occurrence of R^(b) and R^(c) can be independently selected from: Hand —C(O)(C₁₋₄ alkyl). For example, one of R^(b) and R^(c) is H, and theother is —C(O)(C₁₋₄ alkyl) (e.g., —C(O)(CH₃).

Each occurrence of R^(b) and R^(c) can be independently selected from:C₁₋₄ alkyl and —C(O)(C₁₋₄ alkyl). For example, one of R^(b) and R^(c) isC₁₋₄ alkyl (e.g., CH₃), and the other is —C(O)(C₁₋₄ alkyl) (e.g.,—C(O)(CH₃).

R⁶ can be CO₂R^(a). R^(a) can be C₁₋₈ alkyl optionally substituted with—OH, —NH₂, —NH(C₁₋₃ alkyl), —N(C₁₋₃ alkyl)₂, —N(H)(C(═O)C₁₋₄ alkyl), orcyano; e.g., R^(a) can be unsubstituted C₁₋₆ alkyl (e.g., CH₃ orCH₂CH₃).

R⁶ can be —OH (in certain embodiments, R² is —CH₂CH₂CH₂OH).

X can be unbranched chain C₂₋₄ alkylene. In some embodiments, X is anunbranched chain C₅₋₆ alkylene.

One of R³ and R⁴ (e.g., R⁴) can be hydrogen, and the other (e.g., R³)can be a substituent other than hydrogen.

One of R³ and R⁴ (e.g., R⁴) can be hydrogen, and the other (e.g., R³)can be halo or CO₂R^(a).

One of R³ and R⁴ (e.g., R⁴) can be hydrogen, and the other (e.g., R³)can be halo (e.g., Br).

One of R³ and R⁴ (e.g., R⁴) can be hydrogen, and the other (e.g., R³)can be CO₂R^(a). R^(a) can be C₁₋₈ alkyl optionally substituted with—OH, —NH₂, —NH(C₁₋₃ alkyl), —N(C₁₋₃ alkyl)₂, —N(H)(C(═O)C₁₋₄ alkyl), orcyano; e.g., R^(a) can be unsubstituted C₁₋₆ alkyl (e.g., CH₃ orCH₂CH₃).

R³ can be 3-pyrazolyl, and R⁴ can be hydrogen.

R³ can be hydrogen, and R⁴ can be hydrogen.

In another aspect, the invention provides a compound selected from theexemplified examples or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention provides a compound selectedfrom any subset list of compounds or a single compound from theexemplified examples within the scope of any of the above aspects.

Pharmaceutical Compositions and Administration

In some embodiments, a chemical entity (e.g., a compound that modulates(e.g., agonizes or partially agonizes) NLRP3, or a pharmaceuticallyacceptable salt, and/or hydrate, and/or cocrystal, and/or drugcombination thereof) is administered as a pharmaceutical compositionthat includes the chemical entity and one or more pharmaceuticallyacceptable excipients, and optionally one or more additional therapeuticagents as described herein.

In some embodiments, a pharmaceutical composition comprising a compoundof the present invention or a salt thereof, and one or morepharmaceutically acceptable excipients. In certain embodiments, apharmaceutical composition comprising a compound of the presentinvention or a pharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable excipients. In certain embodiments, apharmaceutical composition comprising a therapeutically effective amountof a compound of the present invention or a pharmaceutically acceptablesalt thereof, and one or more pharmaceutically acceptable excipients.

In some embodiments, the chemical entities can be administered incombination with one or more conventional pharmaceutical excipients.Pharmaceutically acceptable excipients include, but are not limited to,ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifyingdrug delivery systems (SEDDS) such as d-α-tocopherol polyethylene glycol1000 succinate, surfactants used in pharmaceutical dosage forms such asTweens, poloxamers or other similar polymeric delivery matrices, serumproteins, such as human serum albumin, buffer substances such asphosphates, tris, glycine, sorbic acid, potassium sorbate, partialglyceride mixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium-chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethyl cellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, andwool fat. Cyclodextrins such as α-, β, and γ-cyclodextrin, or chemicallymodified derivatives such as hydroxyalkylcyclodextrins, including 2- and3-hydroxypropyl-β-cyclodextrins, or other solubilized derivatives canalso be used to enhance delivery of compounds described herein. Dosageforms or compositions containing a chemical entity as described hereinin the range of 0.005% to 100% with the balance made up from non-toxicexcipient may be prepared. The contemplated compositions may contain0.001%-100% of a chemical entity provided herein, in one embodiment0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%.Actual methods of preparing such dosage forms are known, or will beapparent, to those skilled in this art; for example, see Remington: TheScience and Practice of Pharmacy, 22^(nd) Edition (Pharmaceutical Press,London, UK. 2012).

Routes of Administration and Composition Components

In some embodiments, the chemical entities described herein or apharmaceutical composition thereof can be administered to subject inneed thereof by any accepted route of administration. Acceptable routesof administration include, but are not limited to, buccal, cutaneous,endocervical, endosinusial, endotracheal, enteral, epidural,interstitial, intra-abdominal, intra-arterial, intrabronchial,intrabursal, intracerebral, intracistemal, intracoronary, intradermal,intraductal, intraduodenal, intradural, intraepidermal, intraesophageal,intragastric, intragingival, intraileal, intralymphatic, intramedullary,intrameningeal, intramuscular, intraovarian, intraperitoneal,intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial,intratesticular, intrathecal, intratubular, intratumoral, intrauterine,intravascular, intravenous, nasal, nasogastric, oral, parenteral,percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous,sublingual, submucosal, topical, transdermal, transmucosal,transtracheal, ureteral, urethral and vaginal. In certain embodiments, apreferred route of administration is parenteral (e.g., intratumoral). Incertain embodiments, a preferred route of administration is systemic.

Compositions can be formulated for parenteral administration, e.g.,formulated for injection via the intravenous, intramuscular,sub-cutaneous, or even intraperitoneal routes. Typically, suchcompositions can be prepared as injectables, either as liquid solutionsor suspensions; solid forms suitable for use to prepare solutions orsuspensions upon the addition of a liquid prior to injection can also beprepared; and the preparations can also be emulsified. The preparationof such formulations will be known to those of skill in the art in lightof the present disclosure.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions; formulations including sesame oil,peanut oil, or aqueous propylene glycol; and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases the form must be sterile and must be fluid tothe extent that it may be easily injected. It also should be stableunder the conditions of manufacture and storage and must be preservedagainst the contaminating action of microorganisms, such as bacteria andfungi.

The carrier also can be a solvent or dispersion medium containing, forexample, water, ethanol, polyol (for example, glycerol, propyleneglycol, and liquid polyethylene glycol, and the like), suitable mixturesthereof, and vegetable oils. The proper fluidity can be maintained, forexample, by the use of a coating, such as lecithin, by the maintenanceof the required particle size in the case of dispersion, and by the useof surfactants. The prevention of the action of microorganisms can bebrought about by various antibacterial and antifungal agents, forexample, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, andthe like. In many cases, it will be preferable to include isotonicagents, for example, sugars or sodium chloride. Prolonged absorption ofthe injectable compositions can be brought about by the use in thecompositions of agents delaying absorption, for example, aluminummonostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the activecompounds in the required amount in the appropriate solvent with variousof the other ingredients enumerated above, as required, followed byfiltered sterilization. Generally, dispersions are prepared byincorporating the various sterilized active ingredients into a sterilevehicle which contains the basic dispersion medium and the requiredother ingredients from those enumerated above. In the case of sterilepowders for the preparation of sterile injectable solutions, thepreferred methods of preparation are vacuum-drying and freeze-dryingtechniques, which yield a powder of the active ingredient, plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof.

Intratumoral injections are discussed, e.g., in Lammers, et al., “Effectof Intratumoral Injection on the Biodistribution and the TherapeuticPotential of HPMA Copolymer-Based Drug Delivery Systems” Neoplasia.10:788-795 (2006).

Pharmacologically acceptable excipients usable in the rectal compositionas a gel, cream, enema, or rectal suppository, include, withoutlimitation, any one or more of cocoa butter glycerides, syntheticpolymers such as polyvinylpyrrolidone, PEG (like PEG ointments),glycerine, glycerinated gelatin, hydrogenated vegetable oils,poloxamers, mixtures of polyethylene glycols of various molecularweights and fatty acid esters of polyethylene glycol Vaseline, anhydrouslanolin, shark liver oil, sodium saccharinate, menthol, sweet almondoil, sorbitol, sodium benzoate, anoxid SBN, vanilla essential oil,aerosol, parabens in phenoxyethanol, sodium methyl p-oxybenzoate, sodiumpropyl p-oxybenzoate, diethylamine, carbomers, carbopol,methyloxybenzoate, macrogol cetostearyl ether, cocoyl caprylocaprate,isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum,carboxy-metabisulfite, sodium edetate, sodium benzoate, potassiummetabisulfite, grapefruit seed extract, methyl sulfonyl methane (MSM),lactic acid, glycine, vitamins, such as vitamin A and E and potassiumacetate.

In certain embodiments, suppositories can be prepared by mixing thechemical entities described herein with suitable non-irritatingexcipients or carriers such as cocoa butter, polyethylene glycol or asuppository wax which are solid at ambient temperature but liquid atbody temperature and therefore melt in the rectum and release the activecompound. In other embodiments, compositions for rectal administrationare in the form of an enema.

In other embodiments, the compounds described herein or a pharmaceuticalcomposition thereof are suitable for local delivery to the digestive orGI tract by way of oral administration (e.g., solid or liquid dosageforms).

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the chemicalentity is mixed with one or more pharmaceutically acceptable excipients,such as sodium citrate or dicalcium phosphate and/or: a) fillers orextenders such as starches, lactose, sucrose, glucose, mannitol, andsilicic acid, b) binders such as, for example, carboxymethylcellulose,alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c)humectants such as glycerol, d) disintegrating agents such as agar-agar,calcium carbonate, potato or tapioca starch, alginic acid, certainsilicates, and sodium carbonate, e) solution retarding agents such asparaffin, f) absorption accelerators such as quaternary ammoniumcompounds, g) wetting agents such as, for example, cetyl alcohol andglycerol monostearate, h) absorbents such as kaolin and bentonite clay,and i) lubricants such as talc, calcium stearate, magnesium stearate,solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof.In the case of capsules, tablets and pills, the dosage form may alsocomprise buffering agents. Solid compositions of a similar type may alsobe employed as fillers in soft and hard-filled gelatin capsules usingsuch excipients as lactose or milk sugar as well as high molecularweight polyethylene glycols and the like.

In one embodiment, the compositions will take the form of a unit dosageform such as a pill or tablet and thus the composition may contain,along with a chemical entity provided herein, a diluent such as lactose,sucrose, dicalcium phosphate, or the like; a lubricant such as magnesiumstearate or the like; and a binder such as starch, gum acacia,polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or thelike. In another solid dosage form, a powder, marume, solution orsuspension (e.g., in propylene carbonate, vegetable oils, PEG's,poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin orcellulose base capsule). Unit dosage forms in which one or more chemicalentities provided herein or additional active agents are physicallyseparated are also contemplated; e.g., capsules with granules (ortablets in a capsule) of each drug; two-layer tablets; two-compartmentgel caps, etc. Enteric coated or delayed release oral dosage forms arealso contemplated.

Other physiologically acceptable compounds include wetting agents,emulsifying agents, dispersing agents or preservatives that areparticularly useful for preventing the growth or action ofmicroorganisms. Various preservatives are well known and include, forexample, phenol and ascorbic acid.

In certain embodiments the excipients are sterile and generally free ofundesirable matter. These compositions can be sterilized byconventional, well-known sterilization techniques. For various oraldosage form excipients such as tablets and capsules sterility is notrequired. The USP/NF standard is usually sufficient.

In certain embodiments, solid oral dosage forms can further include oneor more components that chemically and/or structurally predispose thecomposition for delivery of the chemical entity to the stomach or thelower GI; e.g., the ascending colon and/or transverse colon and/ordistal colon and/or small bowel. Exemplary formulation techniques aredescribed in, e.g., Filipski, K. J., et al., Current Topics in MedicinalChemistry. 2013, 13, 776-802.

Examples include upper-GI targeting techniques, e.g., Accordion Pill(Intec Pharma), floating capsules, and materials capable of adhering tomucosal walls.

Other examples include lower-GI targeting techniques. For targetingvarious regions in the intestinal tract, several enteric/pH-responsivecoatings and excipients are available. These materials are typicallypolymers that are designed to dissolve or erode at specific pH ranges,selected based upon the GI region of desired drug release. Thesematerials also function to protect acid labile drugs from gastric fluidor limit exposure in cases where the active ingredient may be irritatingto the upper GI (e.g., hydroxypropyl methylcellulose phthalate series,Coateric (polyvinyl acetate phthalate), cellulose acetate phthalate,hydroxypropyl methylcellulose acetate succinate, Eudragit series(methacrylic acid-methyl methacrylate copolymers), and Marcoat). Othertechniques include dosage forms that respond to local flora in the GItract, Pressure-controlled colon delivery capsule, and Pulsincap.

Ocular compositions can include, without limitation, one or more of anyof the following: viscogens (e.g., Carboxymethylcellulose, Glycerin,Polyvinylpyrrolidone, Polyethylene glycol); Stabilizers (e.g., Pluronic(triblock copolymers), Cyclodextrins); Preservatives (e.g., Benzalkoniumchloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zincchloride; Alcon Laboratories, Inc.), Purite (stabilized oxychlorocomplex; Allergan, Inc.)).

Topical compositions can include ointments and creams. Ointments aresemisolid preparations that are typically based on petrolatum or otherpetroleum derivatives. Creams containing the selected active agent aretypically viscous liquid or semisolid emulsions, often eitheroil-in-water or water-in-oil. Cream bases are typically water-washable,and contain an oil phase, an emulsifier and an aqueous phase. The oilphase, also sometimes called the “internal” phase, is generallycomprised of petrolatum and a fatty alcohol such as cetyl or stearylalcohol; the aqueous phase usually, although not necessarily, exceedsthe oil phase in volume, and generally contains a humectant. Theemulsifier in a cream formulation is generally a nonionic, anionic,cationic or amphoteric surfactant. As with other carriers or vehicles,an ointment base should be inert, stable, nonirritating andnon-sensitizing.

In any of the foregoing embodiments, pharmaceutical compositionsdescribed herein can include one or more one or more of the following:lipids, interbilayer crosslinked multilamellar vesicles, biodegradeablepoly(D,L-lactic-co-glycolic acid) [PLGA]-based or poly anhydride-basednanoparticles or microparticles, and nanoporous particle-supported lipidbilayers.

Dosages

The dosages may be varied depending on the requirement of the patient,the severity of the condition being treating and the particular compoundbeing employed. Determination of the proper dosage for a particularsituation can be determined by one skilled in the medical arts. Thetotal daily dosage may be divided and administered in portionsthroughout the day or by means providing continuous delivery.

In some embodiments, the compounds described herein are administered ata dosage of from about 0.001 mg/Kg to about 500 mg/Kg (e.g., from about0.001 mg/Kg to about 200 mg/Kg; from about 0.01 mg/Kg to about 200mg/Kg; from about 0.01 mg/Kg to about 150 mg/Kg; from about 0.01 mg/Kgto about 100 mg/Kg; from about 0.01 mg/Kg to about 50 mg/Kg; from about0.01 mg/Kg to about 10 mg/Kg; from about 0.01 mg/Kg to about 5 mg/Kg;from about 0.01 mg/Kg to about 1 mg/Kg; from about 0.01 mg/Kg to about0.5 mg/Kg; from about 0.01 mg/Kg to about 0.1 mg/Kg; from about 0.1mg/Kg to about 200 mg/Kg; from about 0.1 mg/Kg to about 150 mg/Kg; fromabout 0.1 mg/Kg to about 100 mg/Kg; from about 0.1 mg/Kg to about 50mg/Kg; from about 0.1 mg/Kg to about 10 mg/Kg; from about 0.1 mg/Kg toabout 5 mg/Kg; from about 0.1 mg/Kg to about 1 mg/Kg; from about 0.1mg/Kg to about 0.5 mg/Kg).

Regimens

The foregoing dosages can be administered on a daily basis (e.g., as asingle dose or as two or more divided doses) or non-daily basis (e.g.,every other day, every two days, every three days, once weekly, twiceweeks, once every two weeks, once a month).

In some embodiments, the period of administration of a compounddescribed herein is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks,11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9months, 10 months, 11 months, 12 months, or more. In a furtherembodiment, a period of during which administration is stopped is for 1day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11months, 12 months, or more. In an embodiment, a therapeutic compound isadministered to an individual for a period of time followed by aseparate period of time. In another embodiment, a therapeutic compoundis administered for a first period and a second period following thefirst period, with administration stopped during the second period,followed by a third period where administration of the therapeuticcompound is started and then a fourth period following the third periodwhere administration is stopped. In an aspect of this embodiment, theperiod of administration of a therapeutic compound followed by a periodwhere administration is stopped is repeated for a determined orundetermined period of time. In a further embodiment, a period ofadministration is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks,11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9months, 10 months, 11 months, 12 months, or more. In a furtherembodiment, a period of during which administration is stopped is for 1day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11months, 12 months, or more.

Methods of Treatment

In some embodiments, methods for treating a subject having condition,disease or disorder in which an increase in NLRP3 signaling may correcta deficiency in innate immune activity (e.g., a condition, disease ordisorder associated with an insufficient immune response) thatcontributes to the pathology and/or symptoms and/or progression of thecondition, disease or disorder (e.g., cancer) are provided.

Indications

In any of the methods described herein, the subject can have a cancer.In some examples of any of the methods described herein, the mammal hasbeen identified as having a cancer, or has been diagnosed as having acancer.

Non-limiting examples of cancer include: acute myeloid leukemia,adrenocortical carcinoma, Kaposi sarcoma, lymphoma, anal cancer,appendix cancer, teratoid/rhabdoid tumor, basal cell carcinoma, bileduct cancer, bladder cancer, bone cancer, brain cancer, breast cancer,bronchial tumor, carcinoid tumor, cardiac tumor, cervical cancer,chordoma, chronic lymphocytic leukemia, chronic myeloproliferativeneoplasm, colon cancer, colorectal cancer, craniopharyngioma, bile ductcancer, endometrial cancer, ependymoma, esophageal cancer,esthesioneuroblastoma, Ewing sarcoma, eye cancer, fallopian tube cancer,gallbladder cancer, gastrointestinal carcinoid tumor, gastrointestinalstromal tumor, germ cell tumor, hairy cell leukemia, head and neckcancer, heart cancer, liver cancer, hypopharngeal cancer, pancreaticcancer, kidney cancer, laryngeal cancer, chronic myelogenous leukemia,lip and oral cavity cancer, lung cancer, melanoma, Merkel cellcarcinoma, mesothelioma, mouth cancer, oral cancer, osteosarcoma,ovarian cancer, penile cancer, pharyngeal cancer, prostate cancer,rectal cancer, salivary gland cancer, skin cancer, small intestinecancer, soft tissue sarcoma, testicular cancer, throat cancer, thyroidcancer, urethral cancer, uterine cancer, vaginal cancer, and vulvarcancer.

In certain embodiments, non-limiting examples of cancer include: breastcancer, colon cancer, rectal cancer, colorectal cancer, pancreaticcancer, and prostate cancer.

Methods for diagnosing a subject as having a cancer or identifying amammal as having a cancer are well known in the art. For example, amedical professional (e.g., a physician, a physician's assistant, or atechnician) can diagnose cancer in a mammal by observing one or moresymptoms of cancer in a mammal. Non-limiting examples of symptoms ofcancer include: fatigue, lump or area of thickening felt under the skin,weight change, jaundice, darkening or redness of the skin, sores thatwon't heal, changes to existing moles, changes in bowel or bladderhabits, persistent cough or trouble breathing, difficulty swallowing,hoarseness, persistent indigestion or discomfort after eating,persistent, unexplained muscle or joint pain, persistent, unexplainedfevers or night sweats, and unexplained bleeding or bruising. Methods ofdiagnosing a subject as having a cancer or identifying a subject ashaving a cancer can further include performing one or more diagnostictests (e.g., performing one or more diagnostic tests on a biopsy or ablood sample).

In some examples of any of the methods described herein, a subject canbe a subject having a cancer, a subject diagnosed as having a cancer, ora subject identified as having a cancer that has been unresponsive to apreviously administered treatment for cancer. Diagnostic tests fordiagnosing a subject as having a cancer or identifying a mammal ashaving a cancer are known in the art.

In some embodiments, methods for treating a subject having condition,disease or disorder in which an increase in NLRP3 signaling may correcta deficiency in innate immune activity (e.g., a condition, disease ordisorder associated with an insufficient immune response) thatcontributes to the pathology and/or symptoms and/or progression of thecondition, disease or disorder (e.g., cancer) are provided.

In some embodiments, the present invention provides a method of treatingcancer, wherein the cancer can be any cancer that does not elicit anoptimal innate immune system response.

Innate immune system refers to a part of the immune system consisting ofcells that react to threats for the organism like infections or cancerin an antigen-non-specific way and stimulate the adaptive,antigen-specific immune system. In general, complete removal of thethreat and long-lasting protection (=immunity) requires activity of theadaptive, antigen-specific immune system that in turn depends onstimulation by the innate immune system.

In some embodiments, the present invention provides a method of treatingcase, the cancer is selected based on resistance to T-cell checkpointinhibition, either independent of cancer type and based on failure torespond to previous T-cell checkpoint inhibitor therapy or based oncancer type that is generally resistant to T-cell checkpoint inhibitortherapy such as hormone receptor positive breast cancer, microsatellitestable colon or rectal cancer, pancreatic cancer and prostate cancer.

In certain other embodiments, the present invention provides a method oftreating cancer comprising an NLPR3 agonist of the present invention totreat non-inflamed tumors with low CD8+ T-cell infiltration to enhancetumor immunogenicity and promote inflammatory responses. For example,the combination may be used to treat a solid tumor based on results of abiopsy that demonstrated low CD8+ T-cell infiltration or low expressionof genes produced by CD8+ T-cells.

Resistance to T-cell checkpoint inhibition refers to cancer progressionon therapy or lack of response within 6 months of therapy according toconsensus response criteria for the respective cancer, such as RECIST1.1for most solid tumors.

T-cell infiltration refers to percent of T-cells of all nucleated cellsby immunohistochemistry of tumor biopsy specimens.

CD8+ T-cell infiltration refers to percent of CD8+ cells of allnucleated cells by immunohistochemistry of tumor biopsy specimens.

In addition to immunohistochemistry for quantifying CD8+ T-cells inbiopsy specimens, expression of genes produced by CD8+ T-cells likeinterferon-γ can be measured by quantifying mRNA using for example nextgeneration sequencing and inform about CD8+ T-cell infiltration.Thresholds for low and high CD8+ T-cell infiltration byimmunohistochemistry of mRNA quantifying techniques are being developedby various groups and take the spectrum of CD8+ T-cell infiltrationacross cancers as well as for specific cancers into account.

In any of the methods described herein, the subject can have aninfectious disease. In some examples of any of the methods describedherein, the subject has been identified as having an infectious disease,or has been diagnosed as having an infectious disease. For example, aninfectious disease can be caused by a bacterium, virus, fungus,parasite, or a mycobacterium.

Non-limiting examples of infectious disease include: Acinobacterinfection, actinomycosis, African sleeping sickness, acquiredimmunodeficiency syndrome, amebiasis, anaplasmosis, anthrax,Arcanobacterium haemolyticum infection, Argentine hemorrhagic fever,ascariasis, aspergillosis, astrovirus infection, babesiosis, Bacilluscereus infection, bacterial pneumonia, bacterial vaginosis, Bacteroidesinfection, balantidiasis, Baylisascaris infection, BK virus infection,black piedra, Blastocystic hominis infection, blastomycosis, Bolivianhemorrhagic fever, botulism, Brazilian hemorrhagic fever, brucellosis,bubonic plaque, Burkholderi infection, Buruli ulcer, Calicivirusinfection, camptobacteriosis, candidiasis, cat-scratch disease,cellulitis, Chagas disease, chancroid, chickenpox, chikungunya,chlamydia, Chlamydophila pneumoniae infection, cholera,chromoblastomycosis, clonorchiasis, Clostridium difficile infection,coccidioidomycosis, Colorado tick fever, common cold, Creutzfeldt-Jakobdisease, Crimean-Congo hemorrhagic fever, crytococcosis,cryptosporidiosis, cutaneous larva migrans, cyclosporiasis,cysticercosis, cytomegalovirus infection, dengue fever, Desmodesmusinfection, deintamoebiasis, diphtheria, diphyllobothriasis,dracunculiasis, ebola hemorrhagic fever, echinococcosis, ehrlichiosis,enterobiasis, Enterococcus infection, Enterovirus infection, epidemictyphus, erythema infection, exanthema subitum, fasciolopsiasis,fasciolosis, fatal familial insomnia, filariasis, food poisoning byClostridium myonecrosis, free-living amebic infection, Fusobacteriuminfection, gas gangrene, geotrichosis, Gerstmann-Straussler-Scheinkersyndrome, giardiasis, glanders, gnathostomiasis, gonorrhea, granulomainguinale, Group A streptococcal infection, Group B streptococcalinfection, Haemophilus influenzae infection, hand foot and mouthdisease, hantavirus pulmonary syndrome, Heartland virus disease,Heliobacter pylori infection, hemolytic-uremic syndrome, hemorrhagicfever with renal syndrome, hepatitis A, hepatitis B, hepatitis C,hepatitis D, hepatitis E, herpes simplex, histoplasmosis, hookworminfection, human bocavirus infection, human ewingii ehrlichiosis, humangranulocyte anaplasmosis, human metapneuomovirus infection, humanmonocytic ehrlichiosis, human papillomavirus infection, humanparainfluenza virus infection, hymenolepiasis, Epstein-Barr virusinfectious mononucleosis, influenza, isosporiasis, Kawasaki disease,keratitis, Kingella kingae infection, kuru, lassa fever, Legionnaires'disease, Pontiac fever, leishmaniasis, leprosy, leptospirosis,listeriosis, lyme disease, lymphatic filariasis, lymphocyticchoriomeningitis, malaria, Marburg hemorrhagic fever, measles, MiddleEast respiratory syndrome, melioidosis, meningitis, meningococcaldisease, metagonimiasis, microsporidiosis, molluscum contagiosum,monkeypox, mumps, murine typhus, mycoplasma pneumonia, mycetoma,myiasis, neonatal conjunctivitis, variant Creutzfeldt-Jakob disease,nocardiosis, onchocerciasis, paracoccidioidomycosis, paragonimiasis,pasteurellosis, pediculosis capitis, pediculosis corporis, pediculosispubis, pelvic inflammatory disease, pertussis, plague, pneumonia,poliomyelitis, Prevotella infection, primary amoebicmeningoencephalitis, progressive multifocal leukoencephalopathy,psittacosis, Q fever, rabies, relapsing fever, respiratory syncytialvirus infection, rhinosporidiosis, rhinovirus infection, rickettsialinfection, rickettsialpox, Rift Valley Fever, Rocky Mountain spottedfever, rotavirus infection, rubella, salmonellosis, severe acuterespiratory syndrome, scabies, schistosomiasis, sepsis, shigellosis,shingles, smallpox, sporothrichosis, staphylococcal food poisoning,staphylococcal infection, strongyloidiasis, subacute sclerosingpanencephalitis, syphilis, taeniasis, tetanus, tinea barabe, tineacapitis, tinea corporis, tinea cruris, tinea manum, tinea nigra, tineapedis, tinea unguium, tinea versicolor, toxocariasis, trachoma,toxoplasmosis, trichinosis, trichomoniasis, trichuriasis, tuberculosis,tularemia, typhoid fever, Ureaplasma urealyticum infection, valleyfever, Venezuelan hemorrhagic fever, viral pneumonia, West Nile fever,white piedra, Yersinia psuedotuberculosis infection, yersiniosis, yellowfever, and zygomycosis.

Methods for diagnosing a subject as having an infectious disease, oridentifying a subject as having an infectious disease are well known inthe art. For example, a medical professional (e.g., a physician, aphysician's assistant, or a technician) can diagnose infectious diseasein a subject by observing one or more symptoms of infectious disease ina subject. Non-limiting examples of symptoms of infectious diseaseinclude: fever, diarrhea, fatigue, and muscle aches. Methods ofdiagnosing a mammal as having an infectious disease or identifying asubject as having an infectious disease can further include performingone or more diagnostic tests (e.g., performing one or more diagnostictests on a biopsy or a blood sample). Diagnostic tests for diagnosing asubject as having an infectious disease or identifying a subject ashaving an infectious disease are known in the art.

Combination Therapy

This disclosure contemplates both monotherapy regimens as well ascombination therapy regimens.

In some embodiments, the methods described herein can further includeadministering one or more additional therapies (e.g., one or moreadditional therapeutic agents and/or one or more therapeutic regimens)in combination with administration of the compounds described herein.

In certain embodiments, the methods described herein can further includeadministering one or more additional cancer therapies.

The one or more additional cancer therapies can include, withoutlimitation, surgery, radiotherapy, chemotherapy, toxin therapy,immunotherapy, cryotherapy, cancer vaccines (e.g., HPV vaccine,hepatitis B vaccine, Oncophage, Provenge) and gene therapy, as well ascombinations thereof. Immunotherapy, including, without limitation,adoptive cell therapy, the derivation of stem cells and/or dendriticcells, blood transfusions, lavages, and/or other treatments, including,without limitation, freezing a tumor.

In some embodiments, the one or more additional cancer therapies ischemotherapy, which can include administering one or more additionalchemotherapeutic agents.

In certain embodiments, the additional cancer therapy comprises(chemotherapeutic agent) an immunomodulatory moiety, e.g., an immunecheckpoint inhibitor. In certain of these embodiments, the immunecheckpoint inhibitor targets an immune checkpoint receptor selected fromCTLA-4, PD-1, PD-L1, PD-1-PD-L1, PD-1-PD-L2, T cell immunoglobulin andmucin 3 (TIM3 or HAVCR2), Galectin 9-TIM3, Phosphatidylserine-TIM3,lymphocyte activation gene 3 protein (LAG3), MHC class II-LAG3,4-1BB-4-1BB ligand, OX40-OX40 ligand, GITR, GITR ligand-GITR, CD27,CD70-CD27, TNFRSF25, TNFRSF25-TL1A, CD40L, CD40-CD40 ligand,HVEM-LIGHT-LTA, HVEM, HVEM-BTLA, HVEM-CD160, HVEM-LIGHT,HVEM-BTLA-CD160, CD80, CD80-PDL-1, PDL2-CD80, CD244, CD48-CD244, CD244,ICOS, ICOS-ICOS ligand, B7-H3, B7-H4, VISTA, TMIGD2, HHLA2-TMIGD2,Butyrophilins, including BTNL2, Siglec family, TIGIT and PVR familymembers, KIRs, ILTs and LIRs, NKG2D and NKG2A, MICA and MICB, CD244,CD28, CD86-CD28, CD86-CTLA, CD80-CD28, Phosphatidylserine, TIM3,Phosphatidylserine-TIM3, SIRPA-CD47, VEGF, Neuropilin, CD160, CD30, andCD155 (e.g., CTLA-4 or PD1 or PD-L1) and other immunomodulatory agents,such as interleukin-2 (IL-2), indoleamine 2,3-dioxygenase (IDO), IL-10,transforming growth factor-β (TGFβ), CD39, CD73 Adenosine-CD39-CD73, andCXCR4-CXCL12. See, e.g., Postow, M. J. Clin. Oncol. 33, 1 (2015).

In certain embodiments, the immune checkpoint inhibitor targets animmune checkpoint receptor selected from CTLA-4, PD-1, PD-L1,PD-1-PD-L1, and PD-1-PD-L2.

In certain embodiments, the immune checkpoint inhibitor is selectedfrom: nivolumab (also known as “OPDIVO”; formerly designated 5C4,BMS-936558, MDX-1106, or ONO-4538), pembrolizumab (also known as“KEYTRUDA”, lambrolizumab, and MK-3475. See WO 2008/156712), PDR001(Novartis; see WO 2015/112900), MEDI-0680 (AstraZeneca; AMP-514; see WO2012/145493), cemiplimab (REGN-2810) (Regeneron; see WO 2015/112800),JS001 (TAIZHOU JUNSHI PHARMA; see Si-Yang Liu et al., J. Hematol. Oncol.10:136 (2017)), BGB-A317 (Beigene; see WO 2015/35606 and US2015/0079109), INCSHR1210 (SHR-1210; Jiangsu Hengrui Medicine; see WO2015/085847; Si-Yang Liu et al., J. Hematol. Oncol. 10:136 (2017)),TSR-042 (ANB011; Tesaro Biopharmaceutical; see WO2014/179664), GLS-010(WBP3055; Wuxi/Harbin Gloria Pharmaceuticals; see Si-Yang Liu et al., J.Hematol. Oncol. 10:136 (2017)), AM-0001 (Armo), STI-1110 (SorrentoTherapeutics; see WO 2014/194302), AGEN2034 (Agenus; see WO2017/040790), MGD013 (Macrogenics); IBI308 (Innovent; see WO2017/024465, WO 2017/025016, WO 2017/132825, WO2017/133540); BMS-936559(formerly 12A4 or MDX-1105; see. e.g., U.S. Pat. No. 7,943,743 and WO2013/173223), MPDL3280A (also known as RG7446, atezolizumab, andTECENTRIQ; U.S. Pat. No. 8,217,149; see, also, Herbst et al. (2013) JClin Oncol 31(suppl):3000), durvalumab (IMFINZI; MEDI-4736; AstraZeneca;see WO 2011/066389), avelumab (Pfizer; MSB-0010718C; BAVENCIO; see WO2013/079174), STI-1014 (Sorrento; see WO2013/181634), CX-072 (Cytomx;see WO2016/149201), KN035 (3D Med/Alphamab; see Zhang et al., CellDiscov. 7:3 (March 2017), LY3300054 (Eli Lilly Co.; see, e.g, WO2017/034916), CK-301 (Checkpoint Therapeutics; see Gorelik et al.,AACR:Abstract 4606 (April 2016)); urelumab, PF-05082566, MEDI6469,TRX518, varlilumab, CP-870893, BMS-986016, MGA271, lirilumab, IPH2201,emactuzumab, INCB024360, galunisertib, ulocuplumab, BKT140, Bavituximab,CC-90002, bevacizumab, MNRP1685A, ipilimumab (YERVOY; U.S. Pat. No.6,984,720), MK-1308 (Merck), AGEN-1884 (Agenus Inc.; WO 2016/196237),and tremelimumab (formerly ticilimumab, CP-675,206; AstraZeneca; see,e.g., WO 2000/037504 and Ribas, Update Cancer Ther. 2(3): 133-39(2007)).

In certain embodiments, the immune checkpoint inhibitor is selectedfrom: nivolumab, pembrolizumab, JS001, BGB-A317, INCSHR1210, TSR-042,GLS-010, STI-1110, MGD013, IBI308, BMS-936559, atezolizumab, durvalumab,avelumab, STI-1014, CX-072, KN035, LY3300054, CK-301, urelumab,PF-05082566, MEDI6469, TRX518, varlilumab, BMS-986016, ipilimumab,AGEN-1884, and tremelimumab.

In certain of these embodiments, the immune checkpoint inhibitor isselected from: Urelumab, PF-05082566, MEDI6469, TRX518, Varlilumab,CP-870893, Pembrolizumab (PD1), Nivolumab (PD1), Atezolizumab (formerlyMPDL3280A) (PDL1), MEDI4736 (PD-L1), Avelumab (PD-L 1), PDR001 (PD1),BMS -986016, MGA271, Lirilumab, IPH2201, Emactuzumab, INCB024360,Galunisertib, Ulocuplumab, BKT140, Bavituximab, CC-90002, bevacizumab,and MNRP1685A.

In certain embodiments, the immune checkpoint inhibitor is selectedfrom: nivolumab, ipilimumab, pembrolizumab, atezolizumab, durvalumab andavelumab.

In certain embodiments, the immune checkpoint inhibitor is selectedfrom: nivolumab and ipilimumab.

In certain embodiments, the additional anti-cancer agent(chemotherapeutic agent) is a STING agonist. For example, the STINGagonist can include cyclic di-nucleotides, such as cAMP, cGMP, and cGAMPas well as modified cyclic di-nucleotides that include one or more ofthe following modification features (2′-O/3′-O linkage, phosphorothioatelinkage, adenine and/or guanine analogue, 2′-OH modification (e.g.,—OCH₃ or replacement, e.g., —F or N₃). See, e.g., WO 2014/189805.

In certain embodiments, the additional chemotherapeutic agent is analkylating agent. Alkylating agents are so named because of theirability to alkylate many nucleophilic functional groups under conditionspresent in cells, including, but not limited to cancer cells. In afurther embodiment, an alkylating agent includes, but is not limited to,Cisplatin, carboplatin, mechlorethamine, cyclophosphamide, chlorambucil,ifosfamide and/or oxaliplatin. In an embodiment, alkylating agents canfunction by impairing cell function by forming covalent bonds with theamino, carboxyl, sulfhydryl, and phosphate groups in biologicallyimportant molecules or they can work by modifying a cell's DNA. In afurther embodiment an alkylating agent is a synthetic, semisynthetic orderivative.

In certain embodiments, the additional chemotherapeutic agent is ananti-metabolite. Anti-metabolites masquerade as purines or pyrimidines,the building-blocks of DNA and in general, prevent these substances frombecoming incorporated in to DNA during the “S” phase (of the cellcycle), stopping normal development and division. Anti-metabolites canalso affect RNA synthesis. In an embodiment, an antimetabolite includes,but is not limited to azathioprine and/or mercaptopurine. In a furtherembodiment an anti-metabolite is a synthetic, semisynthetic orderivative.

In certain embodiments, the additional chemotherapeutic agent is a plantalkaloid and/or terpenoid. These alkaloids are derived from plants andblock cell division by, in general, preventing microtubule function. Inan embodiment, a plant alkaloid and/or terpenoid is a vinca alkaloid, apodophyllotoxin and/or a taxane. Vinca alkaloids, in general, bind tospecific sites on tubulin, inhibiting the assembly of tubulin intomicrotubules, generally during the M phase of the cell cycle. In anembodiment, a vinca alkaloid is derived, without limitation, from theMadagascar periwinkle, Catharanthus roseus (formerly known as Vincarosea). In an embodiment, a vinca alkaloid includes, without limitation,Vincristine, Vinblastine, Vinorelbine and/or Vindesine. In anembodiment, a taxane includes, but is not limited, to Taxol, Paclitaxeland/or Docetaxel. In a further embodiment a plant alkaloid or terpemoidis a synthetic, semisynthetic or derivative. In a further embodiment, apodophyllotoxin is, without limitation, an etoposide and/or teniposide.In an embodiment, a taxane is, without limitation, docetaxel and/orortataxel. In an embodiment, a cancer therapeutic is a topoisomerase.Topoisomerases are essential enzymes that maintain the topology of DNA.Inhibition of type I or type II topoisomerases interferes with bothtranscription and replication of DNA by upsetting proper DNAsupercoiling. In a further embodiment, a topoisomerase is, withoutlimitation, a type I topoisomerase inhibitor or a type II topoisomeraseinhibitor. In an embodiment a type I topoisomerase inhibitor is, withoutlimitation, a camptothecin. In another embodiment, a camptothecin is,without limitation, exatecan, irinotecan, lurtotecan, topotecan, BNP1350, CKD 602, DB 67 (AR67) and/or ST 1481. In an embodiment, a type IItopoisomerase inhibitor is, without limitation, epipodophyllotoxin. In afurther embodiment an epipodophyllotoxin is, without limitation, anamsacrine, etoposid, etoposide phosphate and/or teniposide. In a furtherembodiment a topoisomerase is a synthetic, semisynthetic or derivative,including those found in nature such as, without limitation,epipodophyllotoxins, substances naturally occurring in the root ofAmerican Mayapple (Podophyllum peltatum).

In certain embodiments, the additional chemotherapeutic agent is astilbenoid. In a further embodiment, a stilbenoid includes, but is notlimited to, Resveratrol, Piceatannol, Pinosylvin, Pterostilbene,Alpha-Viniferin, Ampelopsin A, Ampelopsin E, Diptoindonesin C,Diptoindonesin F, Epsilon-Vinferin, Flexuosol A, Gnetin H, HemsleyanolD, Hopeaphenol, Trans-Diptoindonesin B, Astringin, Piceid andDiptoindonesin A. In a further embodiment a stilbenoid is a synthetic,semisynthetic or derivative.

In certain embodiments, the additional chemotherapeutic agent is acytotoxic antibiotic. In an embodiment, a cytotoxic antibiotic is,without limitation, an actinomycin, an anthracenedione, ananthracycline, thalidomide, dichloroacetic acid, nicotinic acid,2-deoxyglucose and/or chlofazimine. In an embodiment, an actinomycin is,without limitation, actinomycin D, bacitracin, colistin (polymyxin E)and/or polymyxin B. In another embodiment, an antracenedione is, withoutlimitation, mitoxantrone and/or pixantrone. In a further embodiment, ananthracycline is, without limitation, bleomycin, doxorubicin(Adriamycin), daunorubicin (daunomycin), epirubicin, idarubicin,mitomycin, plicamycin and/or valrubicin. In a further embodiment acytotoxic antibiotic is a synthetic, semisynthetic or derivative.

In certain embodiments, the additional chemotherapeutic agent isselected from endostatin, angiogenin, angiostatin, chemokines,angioarrestin, angiostatin (plasminogen fragment), basement-membranecollagen-derived anti-angiogenic factors (tumstatin, canstatin, orarrestin), anti-angiogenic antithrombin III, signal transductioninhibitors, cartilage-derived inhibitor (CDI), CD59 complement fragment,fibronectin fragment, gro-beta, heparinases, heparin hexasaccharidefragment, human chorionic gonadotropin (hCG), interferonalpha/beta/gamma, interferon inducible protein (IP-10), interleukin-12,kringle 5 (plasminogen fragment), metalloproteinase inhibitors (TIMPs),2-methoxyestradiol, placental ribonuclease inhibitor, plasminogenactivator inhibitor, platelet factor-4 (PF4), prolactin 16 kD fragment,proliferin-related protein (PRP), various retinoids,tetrahydrocortisol-S, thrombospondin-1 (TSP-1), transforming growthfactor-beta (TGF-β), vasculostatin, vasostatin (calreticulin fragment)and the like.

In certain embodiments, the additional chemotherapeutic agent isselected from abiraterone acetate, altretamine, anhydrovinblastine,auristatin, bexarotene, bicalutamide, BMS 184476,2,3,4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl)benzene sulfonamide,bleomycin,N,N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-proly-1-Lproline-t-butylamide,cachectin, cemadotin, chlorambucil, cyclophosphamide,3′,4′-didehydro-4′-deoxy-8′-norvin-caleukoblastine, docetaxol,doxetaxel, cyclophosphamide, carboplatin, carmustine, cisplatin,cryptophycin, cyclophosphamide, cytarabine, dacarbazine (DTIC),dactinomycin, daunorubicin, decitabine dolastatin, doxorubicin(adriamycin), etoposide, 5-fluorouracil, finasteride, flutamide,hydroxyurea and hydroxyureataxanes, ifosfamide, liarozole, lonidamine,lomustine (CCNU), MDV3100, mechlorethamine (nitrogen mustard),melphalan, mivobulin isethionate, rhizoxin, sertenef, streptozocin,mitomycin, methotrexate, taxanes, nilutamide, onapristone, paclitaxel,prednimustine, procarbazine, RPR109881, stramustine phosphate,tamoxifen, tasonermin, taxol, tretinoin, vinblastine, vincristine,vindesine sulfate, and vinflunine.

In certain embodiments, the additional chemotherapeutic agent isplatinum, cisplatin, carboplatin, oxaliplatin, mechlorethamine,cyclophosphamide, chlorambucil, azathioprine, mercaptopurine,vincristine, vinblastine, vinorelbine, vindesine, etoposide andteniposide, paclitaxel, docetaxel, irinotecan, topotecan, amsacrine,etoposide, etoposide phosphate, teniposide, 5-fluorouracil, leucovorin,methotrexate, gemcitabine, taxane, leucovorin, mitomycin C,tegafir-uracil, idarubicin, fludarabine, mitoxantrone, ifosfamide anddoxorubicin. Additional agents include inhibitors of mTOR (mammaliantarget of rapamycin), including but not limited to rapamycin,everolimus, temsirolimus and deforolimus.

In still other embodiments, the additional chemotherapeutic agent can beselected from those delineated in U.S. Pat. No. 7,927,613.

In yet another embodiment, the methods can further include administeringone or both of: (i) one or more anti-fungal agents (e.g., selected fromthe group of bifonazole, butoconazole, clotrimazole, econazole,ketoconazole, luliconazole, miconazole, omoconazole, oxiconazole,sertaconazole, sulconazole, tioconazole, albaconazole, efinaconazole,epoziconazole, fluconazole, isavuconazole, itraconazole, posaconazole,propiconazole, ravusconazole, terconazole, voriconazole, abafungin,amorolfin, butenafine, naftifine, terbinafine, anidulafungin,caspofungin, micafungin, benzoic acid, ciclopirox, flucytosine,5-fluorocytosine, griseofulvin, haloprogin, tolnaflate, undecylenicacid, and balsam of peru) and (ii) one or more antibiotics (e.g.,selected from the group of amikacin, gentamicin, kanamycin, neomycin,netilmicin, tobramycin, paromomycin, streptomycin, spectinomycin,geldanamycin, herbimycin, rifaximin, loracarbef, ertapenem, doripenem,imipenem, cilastatin, meropenem, cefadroxil, cefazolin, cefalotin,cefalothin, cefalexin, cefaclor, cefamandole, cefoxitin, cefprozil,cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime,cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone,cefepime, ceftaroline fosamil, ceftobiprole, teicoplanin, vancomycin,telavancin, dalbavancin, oritavancin, clindamycin, lincomycin,daptomycin, azithromycin, clarithromycin, dirithromycin, erythromycin,roxithromycin, troleandomycin, telithromycin, spiramycin, aztreonam,furazolidone, nitrofurantoin, linezolid, posizolid, radezolid,torezolid, amoxicillin, ampicillin, azlocillin, carbenicillin,cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin,nafcillin, oxacillin, penicillin G, penicillin V, piperacillin,penicillin G, temocillin, ticarcillin, amoxicillin, calvulanate,ampicillin, subbactam, piperacillin, tazobactam, ticarcillin,clavulanate, bacitracin, colistin, polymyxin B, ciprofloxacin, enoxacin,gatifloxacin, gemifloxacin, levofloxacin, lomefloxacin, moxifloxacin,nalidixic acid, norfloxacin, ofloxacin, trovafloxacin, grepafloxacin,sparfloxacin, temafloxacin, mafenide, sulfacetamide, sulfadiazine,silver sulfadiazine, sulfadimethoxine, sulfamethoxazole, sulfanilimide,sulfasalazine, sulfisoxazole, trimethoprim-sulfamethoxazole,sulfonamideochrysoidine, demeclocycline, minocycline, oytetracycline,tetracycline, clofazimine, dapsone, dapreomycin, cycloserine,ethambutol, ethionamide, isoniazid, pyrazinamide, rifampicin, rifabutin,rifapentine, streptomycin, arsphenamine, chloramphenicol, fosfomycin,fusidic acid, metronidazole, mupirocin, platensimycin, quinupristin,dalopristin, thiamphenicol, tigecycyline, tinidazole, trimethoprim, andteixobactin).

In certain embodiments, the second therapeutic agent or regimen isadministered to the subject prior to contacting with or administeringthe chemical entity (e.g., about one hour prior, or about 6 hours prior,or about 12 hours prior, or about 24 hours prior, or about 48 hoursprior, or about 1 week prior, or about 1 month prior).

In other embodiments, the second therapeutic agent or regimen isadministered to the subject at about the same time as contacting with oradministering the chemical entity. By way of example, the secondtherapeutic agent or regimen and the chemical entity are provided to thesubject simultaneously in the same dosage form. As another example, thesecond therapeutic agent or regimen and the chemical entity are providedto the subject concurrently in separate dosage forms.

In still other embodiments, the second therapeutic agent or regimen isadministered to the subject after contacting with or administering thechemical entity (e.g., about one hour after, or about 6 hours after, orabout 12 hours after, or about 24 hours after, or about 48 hours after,or about 1 week after, or about 1 month after).

Patient Selection

In some embodiments, the methods described herein further include thestep of identifying a subject (e.g., a patient) in need of suchtreatment (e.g., by way of biopsy, endoscopy, or other conventionalmethod known in the art). In certain embodiments, the NLRP3 protein canserve as a biomarker for certain types of cancer.

In some embodiments, the chemical entities, methods, and compositionsdescribed herein can be administered to certain treatment-resistantpatient populations (e.g., patients resistant to checkpoint inhibitors).

In some embodiments, the compounds of the present invention may be usedin therapy. In certain embodiments, the present invention provides acombined preparation of a compound of the present invention, or apharmaceutically acceptable salt thereof, and additional therapeuticagent(s) for simultaneous, separate or sequential use in therapy.

In some embodiments, a compound of the present invention, or apharmaceutically acceptable salt thereof, or a pharmaceuticalcomposition containing the same, may be used as a medicament. In certainembodiments, the compounds of the invention may be used for themanufacture of a medicament for the treatment of cancer. In certainembodiments, the compounds of the invention may be used for themanufacture of a medicament for modulating NLRP3 activity. In certainembodiments, the modulating comprises agonizing NLRP3.

Methods of Preparation

As can be appreciated by the skilled artisan, methods of synthesizingthe compounds of the formulae herein will be evident to those ofordinary skill in the art. For example, the compounds described hereincan be synthesized, e.g., using one or more of the methods describedherein and/or using methods described in, e.g., US 2015/0056224.Synthetic chemistry transformations and protecting group methodologies(protection and deprotection) useful in synthesizing the compoundsdescribed herein are known in the art and include, for example, thosesuch as described in R. Larock, Comprehensive Organic Transformations,VCH Publishers (1989); T. W. Greene and RGM. Wuts, Protective Groups inOrganic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M.Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wileyand Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents forOrganic Synthesis, John Wiley and Sons (1995), and subsequent editionsthereof. The starting materials used in preparing the compounds of theinvention are known, made by known methods, or are commerciallyavailable. The skilled artisan will also recognize that conditions andreagents described herein that can be interchanged with alternativeart-recognized equivalents. For example, in many reactions,triethylamine can be interchanged with other bases, such asnon-nucleophilic bases (e.g. diisopropylamine,1,8-diazabicycloundec-7-ene, 2,6-di-tert-butylpyridine, ortetrabutylphosphazene).

The skilled artisan will recognize a variety of analytical methods thatcan be used to characterize the compounds described herein, including,for example, ¹H NMR, heteronuclear NMR, mass spectrometry, liquidchromatography, and infrared spectroscopy. The foregoing list is asubset of characterization methods available to a skilled artisan and isnot intended to be limiting.

To further illustrate the foregoing, the following non-limiting,exemplary synthetic schemes are included. Variations of these exampleswithin the scope of the claims are within the purview of one skilled inthe art and are considered to fall within the scope of the invention asdescribed, and claimed herein. The reader will recognize that theskilled artisan, provided with the present disclosure, and skill in theart is able to prepare and use the invention without exhaustiveexamples.

The following abbreviations have the indicated meanings:

-   -   ACN=acetonitrile    -   Ac₂O=acetic anhydride    -   AcOH=acetic acid    -   BnOH=benzyl alcohol    -   CDCl₃=chloroform-d    -   CD₃OD=methanol-d    -   CH₂Cl₂=dichloromethane    -   CH₃ReO₃=methyltrioxorhenium    -   conc.=concentrated    -   Cs₂CO₃=cesium carbonate    -   CuI=copper (I) iodide    -   d=doublet    -   DCM=dichloromethane    -   DCE=1,2-dichloroethane    -   DIAD=diisopropyl azodicarboxylate    -   DIPEA=N,N-diisopropylethylamine    -   DMF=N,N-dimethylformamide    -   DMSO=dimethylsulfoxide    -   ES=electrospray ionization    -   Et₂O=diethyl ether    -   EtOAc=ethyl acetate    -   EtOH=ethanol    -   equiv=equivalents    -   g=grams    -   h=hours    -   HCl=hydrogen chloride (usually as a solution)    -   H₂O=water    -   H₂O₂=hydrogen peroxide    -   HATU=1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium        3-oxide hexafluorophosphate    -   HCl=hydrogen chloride or hydrochloric acid    -   HPLC=high-performance liquid chromatography    -   I₂=iodine    -   K₂CO₃=potassium carbonate    -   K₂HPO₄=potassium phosphate, dibasic    -   KI=potassium iodide    -   L=liter    -   LC/MS=liquid chromatography mass spectrometer    -   LiBH₄=lithium borohydride    -   m=multiplet    -   m/z=mass to charge ratio    -   M=molar    -   m-CPBA=meta-chloroperoxybenzoic acid    -   mg=milligram(s)    -   MeOH=methanol    -   MHz=megahertz    -   mL=milliliter(s)    -   mmol=millimole(s)    -   NaH=sodium hydride    -   NaHCO₃=sodium hydrogen carbonate    -   Na₂CO₃=sodium carbonate    -   NaOH=sodium hydroxide    -   Na₂SO₄=sodium sulfate    -   NEt₃ and TEA=trimethylamine    -   NH₄OH and NH₃H₂O=ammonium hydroxide    -   NH₄HCO₃=ammonium hydrogen carbonate    -   nm=nanometer    -   PBr₃=phosphorus tribromide    -   PdCl₂(PPh₃)₂=bis(triphenylphosphine)palladium (II) dichloride    -   Pd(dppf)Cl₂=1,1′-Bis(diphenylphosphino)ferrocene    -   Pd(dppf)Cl₂DCM=1,1′-Bis(diphenylphosphino)ferrocene-dichloromethane    -   complex    -   Pd(OH)₂=palladium hydroxide    -   PMB=para-methoxybenzyl    -   POCl₃=phosphorous oxychloride    -   ppm=parts per million    -   Pt=platinum    -   Pt/C=platinum on carbon    -   RP=reverse phase    -   s=singlet    -   t=triplet    -   T3P=1-propanephosphonic anhydride    -   t-BuOK=potassium tert-butoxide    -   TFA=trifluoroacetic acid    -   TLC=thin layer chromatography    -   TsCl and TosCl=para-toluenesulfonyl chloride    -   ° C.═degrees Celsius    -   μm and um=micrometer    -   μmol and umol=micromole(s)

General Procedures for Compounds of the Invention:

The compounds of the present invention can be prepared in a number ofways well known to one skilled in the art of organic synthesis. Thecompounds of the present invention can be synthesized using the methodsdescribed below, together with synthetic methods known in the art ofsynthetic organic chemistry, or variations thereon as appreciated bythose skilled in the art. Preferred methods include, but are not limitedto, those described below.

The compounds of this invention may be prepared using the reactions andtechniques described in this section. The reactions are performed insolvents appropriate to the reagents and materials employed and aresuitable for the transformations being effected. Also, in thedescription of the synthetic methods described below, it is to beunderstood that all proposed reaction conditions, including choice ofsolvent, reaction atmosphere, reaction temperature, duration of theexperiment and work up procedures, are chosen to be the conditionsstandard for that reaction, which should be readily recognized by oneskilled in the art. It is understood by one skilled in the art oforganic synthesis that the functionality present on various portions ofthe molecule must be compatible with the reagents and reactionsproposed. Such restrictions to the substituents that are compatible withthe reaction conditions will be readily apparent to one skilled in theart and alternate methods must then be used. This will sometimes requirea judgment to modify the order of the synthetic steps or to select oneparticular process scheme over another in order to obtain a desiredcompound of the invention. It will also be recognized that another majorconsideration in the planning of any synthetic route in this field isthe judicious choice of the protecting group used for protection of thereactive functional groups present in the compounds described in thisinvention. An authoritative account describing the many alternatives tothe trained practitioner is Greene and Wuts (Protective Groups InOrganic Synthesis, Third Edition, Wiley and Sons, 1999).

Compounds of Formula (I) may be prepared by reference to the methodsillustrated in the following Schemes. As shown therein the end productis a compound having the same structural formula as Formula (I). It willbe understood that any compound of Formula (I) may be produced by theschemes by the suitable selection of reagents with appropriatesubstitution. Solvents, temperatures, pressures, and other reactionconditions may readily be selected by one of ordinary skill in the art.Starting materials are commercially available or readily prepared by oneof ordinary skill in the art. Constituents of compounds are as definedherein or elsewhere in the specification.

The synthesis of the compounds of Formula (I) can be effected using themethods summarized in Schemes 1 and 2.

Step 1

The first step of Scheme 1 begins with a suitably functionalizedquinolinol (i). If desired, the groups R⁷, R⁸, and R¹⁰ may be the groupsR³, R⁴, and W′ found in the final product. Alternatively, one or more ofthese groups may be groups that can be modified at a later stage of thesynthesis, such as bromo. This quinolinol may be purchased commercially,or may be synthesized by methods known to one skilled in the art. Instep 1, the alcohol group of compound (i) may be transformed into ahalogen group or sulfonate ester, such as chloro, bromo, or triflate. Ifthe desired group Z is chloro, this transformation may be effected bytreating compound (i) with a reagent such as phosphoryl chloride in asolvent such as toluene. Alternatively, if the desired group Z is bromo,this transformation may be effected by treating compound (i) with areagent such as phosphorous tribromide in a solvent such as DMF.Alternatively, if the desired group Z is triflate, this transformationmay be effected by treating compound (i) with a reagent such astrifluoromethanesulfonyl chloride, a reagent such as4-dimethylaminopyridine, and a base such as Hunig's base in a solventsuch as dichloromethane.

Step 2

In step 2 of Scheme 1, compound (ii) is transformed into N-oxide (iii)by treatment with an appropriate oxidant, such asmeta-chloroperoxybenzoic acid, in a solvent such as DCM.

Step 3

In step 3 of Scheme 1, compound (iii) is transformed into amine (iv) bytreatment with an appropriate activating reagent, such as tosylchloride, and a source of ammonia, such as ammonium chloride andtriethylamine, in an appropriate solvent, such as DCM.

Step 4

In step 4 of Scheme 1, the halogen Z of compound (iv) is transformedinto group R⁹ of compound (v). The group R⁹ may be the group W desiredin the final compound; alternatively, it may be a group that can betransformed into group W at a later stage of the synthesis. One skilledin the art will recognize that the means to effect this transformationwill depend on the nature of the groups Rand Z. For example, if Z ischloro and the desired group R⁹ is an amine, this transformation may beeffected by heating compound (iv) to a suitable temperature, such as120° C. with an appropriate amine and a base such as Hunig's base in asolvent such as DMSO. Alternatively, if Z is chloro and the desiredgroup R⁹ is an ether, this transformation may be effected by heatingcompound (iv) to a suitable temperature, such as 100° C. with anappropriate alcohol and a base such as potassium tert-butoxide in asolvent such as NMP. Alternatively, if Z is bromo and the desired groupR⁹ is an alkyne, this transformation may be effected by heating compound(iv) to a suitable temperature, such as 70° C., with an appropriatealkyne, copper (I) iodide, an appropriate base, such as Hunig's base,and a suitable palladium source, such astetrakis(triphenylphosphine)palladium(0), in a suitable solvent, such asTHF. Alternatively, if Z is a triflate and the desired group R⁹ is aoptionally substituted alkyl group, this step may be accomplished bytreating compound (iv) with an appropriate alkyl boronic acid or ester,a catalyst such as PdCl₂(dppf)-DCM complex, and a base such as cesiumcarbonate in a solvent such as dioxane.

Steps 5 through 8 of Scheme 1 consist of a series of optional functionalgroup manipulations to convert the substituents R⁷, R⁸, R⁹, and R¹⁰ inintermediate (v) to the substituents R³, R, W, and W′ desired in thefinal compound (ix). One skilled in the art will recognize that some orall of these steps may not be necessary depending on the groups found incompounds (v) and (ix). One skilled in the art will also recognize that,for some substrates, these steps may be performed in alternative order.

Step 5

Step 5 of Scheme 1 is an optional step or series of steps to transformthe group R⁷ in intermediate (v) to the group R³ found in molecule (vi).For example, if R⁷ is bromo and the desired group R³ is an aromatic orheteroaromatic group, this transformation may be effected by reactingintermediate (v) with an optionally protected aromatic or heteroaromaticboronic acid or boronic ester, a catalyst such as PdCl₂(dppf)-DCMcomplex, and a base such as tripotassium phosphate in a solvent mixturesuch as dioxane and water. If the group installed contains a protectinggroup, a further optional step may be conducted to remove thatprotecting group under appropriate conditions if desired. For example,if the group installed was a pyrazole with a tetrohydropyran protectinggroup, the tetrohydropyran may be removed by reaction with an acid suchas trifluoroacetic acid in a solvent such as dichloromethane.Alternatively, if R⁷ is bromo and the desired group R³ is an aromatic orheteroaromatic group, this transformation may be effected by reactingintermediate (v) first with a compound such as PdCl₂(dppf)-DCM complexbis(pinacolato)diboron, a reagent such as potassium acetate, and acatalyst such as PdCl₂(dppf)-DCM complex in a solvent such as dioxane,then reacting the resulting boronic ester with an appropriate aryl orheteroaryl halide, a base such as sodium carbonate, and a catalyst suchas tetrakis(triphenylphosphine)palladium(0) in an appropriate solventmixture such as dioxane and water. Alternatively, if R⁷ is bromo and thedesired group R³ is a heterocycle linked through a nitrogen atom, thisstep may be effected by reaction of intermediate (v) with theappropriate heterocycle in the presence of a copper source such ascopper (I) iodide, a base such as sodium carbonate, and a ligand such asN,N′-dimethylethane-1,2-diamine in an appropriate solvent such as DMSO.

Step 6

Step 6 of Scheme 1 is an optional step or series of steps to transformthe group R⁹ in intermediate (vi) to the group W found in molecule(vii). For example, if the group R⁹ contains a Boc-protected amine andthe desired group W contains an amide, this transformation may beaccomplished by first removing the Boc group with a suitable combinationof acid and solvent, such as hydrochloric acid and dioxane, then formingthe desired amide by reaction with the appropriate carboxylic acid, acoupling agent such as T3P, and a base such as triethylamine in asolvent such as DMF. Alternatively, if the group R⁹ contains anunsaturated group such as an alkyne, and the desired group W is fullysaturated, this transformation may be effected by reaction with hydrogenand a suitable catalyst such as palladium on carbon.

Step 7

Step 7 of Scheme 1 is an optional step or series of steps to transformthe group R′ in intermediate (vii) to the group R found in molecule(viii).

Step 8

Step 8 of Scheme 1 is an optional step or series of steps to transformthe group R¹⁰ in intermediate (vii) to the group W′ found in molecule(ix). For example, if the group R¹⁰ contains an alcohol protected with abenzyl ether, and the desired group W′ is the corresponding alcohol,this transformation may be effected by reaction with a suitable acid,such as hydrochloric acid. If group R¹⁰ contains an alcohol, and thedesired group W′ contains an amine at the same location, thistransformation may be effected by first reacting intermediate (vii) witha reagents such as thionyl chloride in a solvent such asdichloromethane, then by reacting the resulting chloride with an aminesuch as ethylamine, sodium iodide, and a base such as potassiumcarbonate in a solvent such as acetonitrile.

One skilled in the art will recognize that a number of these steps maybe performed in alternative order, depending on the groups desired inthe final molecule (ix). For example, for some molecules, thetransformation of the group R⁷ to R³ described in Step 5 may beconducted prior to the transformation of the group Z to the group R⁹described in Step 4.

As an alternative to the route described in Scheme 1, some compounds ofFormula (I) may be accessed by the route described in Scheme 2.

Step 1

Step 1 of Scheme 2 begins with a suitably functionalized aminobenzaldehyde (x) and a suitably functionalized nitrile (xi). If desired,the groups R⁷, R⁸, and R¹⁰ may be the groups R³, R⁴, and W′ found in thefinal product. Alternatively, one or more of these groups may be groupsthat can be modified at a later stage of the synthesis, such as bromo.These compounds may be purchased commercially, or may be synthesized bymethods known to one skilled in the art. Step 1 of Scheme X involvesreaction of (x) and (xi) in the presence of a suitable combination ofbase and solvent, such as potassium tert-butoxide in DMSO or sodiumhydroxide in ethanol, to form aminoquinoline (xii).

Steps 2 through 4 of Scheme 2 consist of a series of optional functionalgroup manipulations to convert the substituents R⁷, R⁸, and R¹⁰ inintermediate (xii) to the substituents R³, R⁴, and W′ desired in thefinal compound (xv). One skilled in the art will recognize that some orall of these steps may not be necessary, depending on the groups foundin compounds (v) and (x). One skilled in the art will also recognizethat, for some substrates, these steps may be performed in alternativeorder.

Step 2

Step 2 of Scheme 2 is an optional step or series of steps to transformthe group R⁷ in intermediate (xii) to the group R³ found in molecule(xiii). For example, if R⁷ is bromo and the desired group R³ is anaromatic or heteroaromatic group, this transformation may be effected byreacting intermediate (xii) with an optionally protected aromatic orheteroaromatic boronic acid or boronic ester, a catalyst such asPdCl₂(dppf)-DCM complex, and a base such as tripotassium phosphate in asolvent mixture such as dioxane and water. If the group installedcontains a protecting group, a further optional step may be conducted toremove that protecting group under appropriate conditions if desired.For example, if the group installed was a pyrazole with atetrohydropyran protecting group, the tetrohydropyran may be removed byreaction with an acid such as trifluoroacetic acid in a solvent such asdichloromethane.

Step 3

Step 3 of Scheme 2 is an optional step or series of steps to transformthe group R₈ in intermediate (xiii) to the group R⁴ found in molecule(xiv).

Step 4

Step 4 of Scheme 2 is an optional step or series of steps to transformthe group R¹⁰ in intermediate (xiv) to the group W′ found in molecule(xv). For example, if the group R¹⁰ contains an alcohol protected with abenzyl ether, and the desired group W′ is the corresponding alcohol,this transformation may be effected by reaction with a suitable acid,such as hydrochloric acid. If group R¹⁰ contains an alcohol, and thedesired group W′ is an amine, this transformation may be effected byfirst reacting intermediate (xiv) with a reagents such as thionylchloride in a solvent such as dichloromethane, then by reacting theresulting chloride with an amine such as ethylamine, sodium iodide, anda base such as potassium carbonate in a solvent such as acetonitrile.

Chemical shifts are reported in parts per million (ppm) downfield frominternal tetramethylsilane (TMS) or from the position of TMS inferred bythe deuterated NMR solvent. Apparent multiplicities are reported as:singlet-s, doublet-d, triplet-t, quartet-q, or multiplet-m. Peaks whichexhibit broadening are further denoted as br. Integrations areapproximate. It should be noted that integration intensities, peakshapes, chemical shifts and coupling constants can be dependent onsolvent, concentration, temperature, pH, and other factors. Further,peaks which overlap with or exchange with water or solvent peaks in theNMR spectrum may not provide reliable integration intensities. In somecases, NMR spectra are obtained using water peak suppression, which mayresult in overlapping peaks not being visible or having altered shapeand/or integration.

Example 1. Synthesis of Compound 101

Step 1: Synthesis of 7-(benzyloxy)heptanenitrile

In a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen was placed a solution of BnOH (1.6 g, 14.80 mmol,1.00 equiv) in N,N-dimethylformamide (60 mL). This was followed by theaddition of sodium hydride (1.02 g, 29.75 mmol, 2.00 equiv) in severalbatches at 0° C. The resulting solution was stirred for 30 minutes at 0°C. in a water/ice bath. To this was added 7-bromoheptanenitrile (2.8 g,14.73 mmol, 1.00 equiv), in portions at 0° C. The resulting solution wasallowed to react, with stirring, for an additional 16 hours at roomtemperature. The reaction was then quenched by the addition of 500 mL ofwater. The resulting solution was extracted with ethyl acetate (2×500mL) and the combined organic layers were concentrated under vacuum. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (50:1). This resulted in 1.87 g (58%) of7-(benzyloxy)heptanenitrile as a yellow solid.

Step 2: Synthesis of 3-[5-(benzyloxy)pentyl]-7-bromoquinolin-2-amine

In a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen was placed a solution of7-(benzyloxy)heptanenitrile (3.05 g, 14.04 mmol, 1.00 equiv) inN,N-dimethylformamide (50 mL). This was followed by the addition oft-BuOK (4.73 g, 42.15 mmol, 3.00 equiv) in several batches at 0° C. Theresulting solution was stirred for 15 minutes at 0° C. in a water/icebath. To this was added 2-amino-4-bromobenzaldehyde (2.8 g, 14.00 mmol,1.00 equiv) in several batches at 0° C. The resulting solution wasallowed to react, with stirring, for an additional 3 hours at roomtemperature. The reaction was then quenched by the addition of 200 mL ofwater. The resulting solution was extracted with ethyl acetate (2×300mL) and the combined organic layers were concentrated under vacuum. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (40:1). This resulted in 1.87 g (33%) of3-[5-(benzyloxy)pentyl]-7-bromoquinolin-2-amine as a yellow solid.LC-MS: (ES, m/z): [M+H]⁺=399.1.

Step 3: Synthesis of3-[5-(benzyloxy)pentyl]-7-(1H-pyrazol-3-yl)quinolin-2-amine (Compound106)

Into a 30-mL sealed tube purged and maintained with an inert atmosphereof nitrogen, was placed a solution of3-[5-(benzyloxy)pentyl]-7-bromoquinolin-2-amine (850 mg, 2.13 mmol, 1.00equiv) in dioxane/H₂O (10:1) (15 mL). To the solution were added3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (828.6 mg, 4.27mmol, 2.00 equiv), Cs₂CO₃ (2.78 g, 8.53 mmol, 4.00 equiv) andPdCl₂(dppf) DCM adduct (349 mg, 0.43 mmol, 0.20 equiv). The resultingsolution was stirred for 16 hours at 90° C. in an oil bath. Theresulting mixture was concentrated under vacuum. The residue was appliedonto a silica gel column with dichloromethane/methanol (30:1). Thisresulted in 559 mg (68%) of3-[5-(benzyloxy)pentyl]-7-(1H-pyrazol-3-yl)quinolin-2-amine as a yellowsolid. LC-MS: (ES, m/z): [M+H]+=387.2.

Step 4: Synthesis of5-[2-amino-7-(1H-pyrazol-3-yl)quinolin-3-yl]pentan-1-ol (Compound 101)

Into a 50-mL round-bottom flask, was placed a solution of3-[5-(benzyloxy)pentyl]-7-(1H-pyrazol-3-yl)quinolin-2-amine (350 mg,0.91 mmol, 1.00 equiv) in concentrated hydrogen chloride (8 mL). Theresulting solution was stirred for 1 h at 50° C. in an oil bath. Theresulting mixture was concentrated under vacuum. The crude product waspurified by Prep-HPLC with the following conditions (HPLC-10): Column,XBridge Shield RP18 OBD Column, 19*250 mm, 10 um; mobile phase, Water(10 mmol/L NH₄HCO₃) and MeCN (27.0% MeCN up to 60.0% in 8 min);Detector, UV 254/210 nm. This resulted in 59.8 mg (22%) of5-[2-amino-7-(1H-pyrazol-3-yl)quinolin-3-yl]pentan-1-ol as a whitesolid. LC-MS: (ES, m/z): [M+H]⁺=297.2. H-NMR: ¹H NMR (300 MHz, CD₃OD-d₄)δ 7.85 (br s, 1H), 7.73 (s, 1H), 7.65-7.62 (m, 3H), 6.71 (d, J=2.1 Hz,1H), 3.55 (t, J=6.3 Hz, 2H), 2.63 (t, J=7.5 Hz, 2H), 1.78-1.67 (m, 2H),1.64-1.53 (m, 2H), 1.51-1.46 (m, 2H).

Example 2: Preparation of3-[2-amino-7-(1H-pyrazol-3-yl)quinolin-3-yl]propan-1-ol (Compound 103)

Step 1: Synthesis of 5-(benzyloxy)pentanenitrile

In a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen was placed a solution of phenylmethanol (3.02 g,27.93 mmol, 1.00 equiv) in N,N-dimethylformamide (50 mL). This wasfollowed by the addition of sodium hydride (1.92 g, 56.00 mmol, 2.00equiv, 70%) in several batches at 0° C. The resulting solution wasstirred for 30 minutes at 0° C. in an ice water bath. To this was added5-bromopentanenitrile (4.5 g, 27.77 mmol, 1.00 equiv), in portions at 0°C. The resulting solution was allowed to react, with stirring, for anadditional 3 h at room temperature. The reaction was then quenched bythe addition of 200 mL of water. The resulting solution was extractedwith ethyl acetate (2×300 mL) and the combined organic layers wereconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (50:1). This resulted in 700mg (13%) of 5-(benzyloxy)pentanenitrile as a yellow oil.

Step 2: Synthesis of 3-[3-(benzyloxy)propyl]-7-bromoquinolin-2-amine

In a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen was placed a solution of5-(benzyloxy)pentanenitrile (2.05 g, 10.83 mmol, 1.00 equiv) inN,N-dimethylformamide (50 mL). This was followed by the addition oft-BuOK (3.641 g, 32.45 mmol, 3.00 equiv) in several batches at 0° C. Theresulting solution was stirred for 15 min at 0° C. in a water/ice bath.To this was added 2-amino-4-bromobenzaldehyde (2.15 g, 10.75 mmol, 1.00equiv) in several batches at 0° C. The resulting solution was allowed toreact, with stirring, for an additional 3 hours at room temperature. Thereaction was then quenched by the addition of 200 mL of water. Theresulting solution was extracted with ethyl acetate (2×300 mL) and thecombined organic layers were concentrated under vacuum. The residue wasapplied onto a silica gel column with ethyl acetate/petroleum ether(30:1). This resulted in 1.3 g (32%) of3-[3-(benzyloxy)propyl]-7-bromoquinolin-2-amine as yellow oil. LC-MS:(ES, m/z): [M+H]⁺=371.3

Step 3: Synthesis of3-[3-(benzyloxy)propyl]-7-(1H-pyrazol-3-yl)quinolin-2-amine (Compound104)

In a 15-mL sealed tube purged and maintained with an inert atmosphere ofnitrogen was placed a solution of3-[3-(benzyloxy)propyl]-7-bromoquinolin-2-amine (360 mg, 0.97 mmol, 1.00equiv) in Dioxane/H₂O (10:1) (8 mL). To the solution were added3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (377.6 mg, 1.95mmol, 2.00 equiv), Cs₂CO₃ (1.26 g, 3.87 mmol, 4.00 equiv) andpdCl₂(dppf) DCM adduct (159 mg, 0.19 mmol, 0.20 equiv). The resultingsolution was stirred for 16 hours at 90° C. in an oil bath. Theresulting mixture was concentrated under vacuum. The residue was appliedonto a silica gel column with dichloromethane/methanol (25:1). Thisresulted in 249 mg (72%) of3-[3-(benzyloxy)propyl]-7-(1H-pyrazol-3-yl)quinolin-2-amine as a yellowsolid. LC-MS: (ES, m/z): [M+H]⁺=359.2

Step 4. Synthesis of3-[2-amino-7-(1H-pyrazol-3-yl)quinolin-3-yl]propan-1-ol (Compound 103)

In a 50-mL round-bottom flask was placed a solution of3-[3-(benzyloxy)propyl]-7-(1H-pyrazol-3-yl)quinolin-2-amine (400 mg,1.12 mmol, 1.00 equiv) in concentrated hydrogen chloride (10 mL). Theresulting solution was stirred for 40 minutes at 50° C. in an oil bath.The resulting mixture was concentrated under vacuum. The crude productwas purified by Prep-HPLC with the following conditions (HPLC-10):Column, X Bridge Shield RP18 OBD Column, 19*250 mm, 10 um; mobile phase,Water (10 mmol/L NH₄HCO₃) and MeCN (6.0% meCN up to 55.0% in 8 min);Detector, UV 254/210 nm. This resulted in 41.4 mg (14%) of3-[2-amino-7-(1H-pyrazol-3-yl)quinolin-3-yl]propan-1-ol as a yellowsolid. LC-MS: (ES, m/z): [M+H]⁺=269.2. ¹H NMR (300 MHz, DMSO-d₆) δ 12.86(s, 1H), 7.82-7.79 (m, 2H), 7.66-7.59 (m, 3H), 6.74 (s, 1H), 6.21 (br s,2H), 4.52 (t, J=5.1 Hz, 1H), 3.49-3.43 (m, 2H), 2.57 (t, J=7.5 Hz, 2H),1.77-1.72 (m, 2H).

Example 3: Preparation of4-[2-amino-7-(1H-pyrazol-3-yl)quinolin-3-yl]butan-1-ol (Compound 102)

Step 1: Synthesis of 6-(benzyloxy)hexanenitrile

In a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen was placed a solution of BnOH (3.22 g, 29.78mmol, 1.00 equiv) in N,N-dimethylformamide (80 mL). This was followed bythe addition of sodium hydride (2.05 g, 59.79 mmol, 2.00 equiv) inseveral batches at 0° C. The resulting solution was stirred for 30minutes at 0° C. in a water/ice bath. To this was added6-bromohexanenitrile (5.2 g, 29.54 mmol, 1.00 equiv) in portions at 0°C. The resulting solution was allowed to react, with stirring, for anadditional 3 hours at room temperature. The reaction was then quenchedby the addition of 500 mL of water. The resulting solution was extractedwith ethyl acetate (3×500 mL) and the combined organic layers wereconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (60:1). This resulted in 1.06g (18%) of 6-(benzyloxy)hexanenitrile as yellow oil.

Step 2. Synthesis of 3-[4-(benzyloxy)butyl]-7-bromoquinolin-2-amine

In a 250-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a solution of6-(benzyloxy)hexanenitrile (2.3 g, 11.31 mmol, 1.00 equiv) inN,N-dimethylformamide (50 mL). This was followed by the addition oft-BuOK (3.81 g, 33.95 mmol, 3.00 equiv) in several batches at 0° C. Theresulting solution was stirred for 15 minutes at 0° C. in a water/icebath. To this was added 2-amino-4-bromobenzaldehyde (2.25 g, 11.25 mmol,1.00 equiv) in several batches at 0° C. The resulting solution wasallowed to react, with stirring, for an additional 3 hours at roomtemperature. The reaction was then quenched by the addition of 200 mL ofwater. The resulting solution was extracted with ethyl acetate (2×300mL) and the combined organic layers were concentrated under vacuum. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (40:1). This resulted in 1.8 g (41%) of3-[4-(benzyloxy)butyl]-7-bromoquinolin-2-amine as yellow oil. LC-MS:(ES, m/z): [M+H]⁺=385.1.

Step 3: Synthesis of3-[4-(benzyloxy)butyl]-7-(1H-pyrazol-3-yl)quinolin-2-amine (Compound105)

In a 30-mL sealed tube purged and maintained with an inert atmosphere ofnitrogen was placed a solution of3-[4-(benzyloxy)butyl]-7-bromoquinolin-2-amine (1.37 g, 3.56 mmol, 1.00equiv) in dioxane/H₂O (10:1) (15 mL). To the solution were added3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.38 g, 7.11 mmol,2.00 equiv), Cs₂CO₃ (4.64 g, 14.24 mmol, 4.00 equiv) and PdCl₂(dppf)Cl₂DCM adduct (583 mg, 0.71 mmol, 0.20 equiv). The resulting solution wasstirred for 16 hours at 90° C. in an oil bath. The resulting mixture wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn with dichloromethane/methanol (35:1). This resulted in 1 g (76%)of 3-[4-(benzyloxy)butyl]-7-(1H-pyrazol-3-yl)quinolin-2-amine as ayellow solid. LC-MS: (ES, m/z): [M+H]⁺=373.2.

Step 4: Synthesis of4-[2-amino-7-(1H-pyrazol-3-yl)quinolin-3-yl]butan-1-ol (Compound 102)

In a 100-mL round-bottom flask was placed a solution of3-[4-(benzyloxy)butyl]-7-(1H-pyrazol-3-yl)quinolin-2-amine (400 mg, 1.07mmol, 1.00 equiv) in concentrated hydrogen chloride (10 mL). Theresulting solution was stirred for 40 minutes at 50° C. in an oil bath.The pH value of the solution was adjusted to 8 with NH₄OH. The resultingmixture was concentrated under vacuum. The crude product was purified byPrep-HPLC with the following conditions (HPLC-10): Column, XBridgeShield RP18 OBD Column, 19*250 mm, 10 um; mobile phase, Water (10 mmol/LNH₄HCO₃) and MeCN (18.0% MeCN up to 40.0% in 9 min); Detector, UV254/210 nm. This resulted in 64.7 mg (21%) of4-[2-amino-7-(1H-pyrazol-3-yl)quinolin-3-yl]butan-1-ol as a white solid.LC-MS: (ES, m/z): [M+H]⁺=283.2. ¹H NMR (300 MHz, DMSO-d₆) δ 12.89 (br s,1H), 7.82 (s, 1H), 7.68-7.58 (m, 4H), 6.74 (s, 1H), 6.24 (s, 2H), 4.38(t, J=5.1 Hz, 1H), 3.45-3.50 (m, 2H), 2.54 (t, J=7.5 Hz, 2H), 1.67-1.45(m, 4H).

Example 4: Preparation of3-[4-amino-7-(1H-pyrazol-3-yl)-[1,3]oxazolo[4,5-c]quinolin-2-yl]propan-1-ol(Compound 107)

Step 1: Synthesis of 7-(1H-pyrazol-3-yl)quinolin-4-ol

In a 500-ml, round-bottom flask purged and maintained with an inertatmosphere of nitrogen was placed a solution of 7-bromoquinolin-4-ol(11.2 g, 49.99 mmol, 1.00 equiv) in dioxane (250 mL) and water (50 mL).To the solution were added sodium carbonate (15.9 g, 150.01 mmol, 3.00equiv), 3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (19.4 g,99.98 mmol, 2.00 equiv), and Pd(PPh₃)₄ (5 g, 4.33 mmol, 0.10 equiv). Theresulting solution was stirred for 16 hours at 90° ° C. in an oil bath.The resulting mixture was concentrated under vacuum. The residue wasapplied onto a silica gel column with DCM/MeOH (0-10%). This resulted in8.44 g (76%) of 7-(1H-pyrazol-3-yl)quinolin-4-ol as a light yellowsolid. LC-MS: (ES, m/z): [M+H]⁺=212.2.

Step 2: Synthesis of 4-bromo-7-(1H-pyrazol-3-yl)quinoline

In a 500-ml, round-bottom flask purged and maintained with an inertatmosphere of nitroge, was placed a solution of7-(1H-pyrazol-3-yl)quinolin-4-ol (8.44 g, 39.96 mmol, 1.00 equiv) inN,N-dimethylformamide (200 mL). This was followed by the addition ofPBr₃ (21.6 g, 79.80 mmol, 2.00 equiv) dropwise with stirring at 0° C.The resulting solution was stirred for 30 minutes at room temperature.The reaction was then quenched by the addition of ice water. The pH ofthe solution was adjusted to 10 with sodium hydroxide. The resultingsolution was extracted with ethyl acetate (3×500 mL) and the organiclayers combined. The solution was washed with brine (3×200 mL), driedover anhydrous sodium sulfate, and concentrated under vacuum. Theresidue was applied onto a silica gel column with ethylacetate/petroleum ether (0-80%). This resulted in 5.3 g (48%) of4-bromo-7-(1H-pyrazol-3-yl)quinoline as a light yellow solid. LC-MS:(ES, m/z): [M+H]⁺=275.1.

Step 3: Synthesis of4-[3-(benzyloxy)prop-1-yn-1-yl]-7-(1H-pyrazol-3-yl)quinolone

In a 30-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen was placed a solution of4-bromo-7-(1H-pyrazol-3-yl)quinoline (548 mg, 2.00 mmol, 1.00 equiv) intetrahydrofuran (20 mL). To the solution were added Hunig's base (1.29g, 10.00 mmol, 5.00 equiv), [(prop-2-yn-1-yloxy)methyl]benzene (584 mg,3.99 mmol, 2.00 equiv), CuI (7.4 mg, 0.04 mmol, 0.20 equiv), andPd(PPh₃)₄(231 mg, 0.20 mmol, 0.10 equiv). The resulting solution wasstirred for 16 hours at 70° C. in an oil bath. The resulting mixture wasconcentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (0-70%). This resulted in 500mg (74%) of 4-[3-(benzyloxy)prop-1-yn-1-yl]-7-(1H-pyrazol-3-yl)quinolineas a light yellow solid. LC-MS: (ES, m/z): [M+H]⁺=340.4.

Step 4: Synthesis of4-[3-(benzyloxy)propyl]-7-(1H-pyrazol-3-yl)quinoline

In a 100-mL round-bottom flask was placed a solution of4-[3-(benzyloxy)prop-1-yn-1-yl]-7-(1H-pyrazol-3-yl)quinoline (420 mg,1.24 mmol, 1.00 equiv) in methanol (20 mL). To the solution was addedpalladium on carbon (210 mg). The resulting solution was degassed andback filled with hydrogen. Then the solution was stirred for 16 hours atroom temperature. The solids were filtered out. The resulting mixturewas concentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate/petroleum ether (0-80%). This resulted in 343mg (81%) of 4-[3-(benzyloxy)propyl]-7-(1H-pyrazol-3-yl)quinoline as alight yellow solid. LC-MS: (ES, m/z): [M+H]⁺=344.4.

Step 5: Synthesis of4-[3-(benzyloxy)propyl]-7-(1H-pyrazol-3-yl)quinolin-1-ium-1-olate

Into a 50-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed a solution of4-[3-(benzyloxy)propyl]-7-(1H-pyrazol-3-yl)quinoline (343 mg, 1.00 mmol,1.00 equiv) in dichloromethane (10 mL). To the solution was added m-CPBA(344 mg, 1.99 mmol, 2.00 equiv). The resulting solution was stirred for5 h at room temperature. The reaction was then quenched by the additionof 10 mL of Na₂S₂O₄ aqueous. The resulting solution was extracted withDCM:MeOH (10:1, 3×10 mL) and the organic layers combined. The solutionwas dried over anhydrous sodium sulfate and concentrated under vacuum.The residue was applied onto a silica gel column withdichloromethane/methanol (0-5%). This resulted in 240 mg (67%) of4-[3-(benzyloxy)propyl]-7-(1H-pyrazol-3-yl)quinolin-1-ium-1-olate as alight yellow solid. LC-MS: (ES, m/z): [M+H]⁺=360.4.

Step 6: Synthesis of4-[3-(benzyloxy)propyl]-7-(1H-pyrazol-3-yl)quinolin-2-amine (Compound108)

Into a 50-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed4-[3-(benzyloxy)propyl]-7-(1H-pyrazol-3-yl)quinolin-1-ium-1-olate (240mg, 0.67 mmol, 1.00 equiv) in dichloromethane (6 mL). To the solutionwere added NH₄OH (3 mL) and TsCl (176 mg, 2.00 equiv). The resultingsolution was stirred for 16 h at room temperature. The resulting mixturewas concentrated under vacuum. The residue was applied onto a silica gelcolumn with dichloromethane/methanol (0-10%). This resulted in 220 mg(92%) of 4-[3-(benzyloxy)propyl]-7-(1H-pyrazol-3-yl)quinolin-2-amine asa light yellow solid. LC-MS: (ES, m/z): [M+H]⁺=359.4.

Step 7: Synthesis of3-[4-amino-7-(1H-pyrazol-3-yl)-[1,3]oxazolo[4,5-c]quinolin-2-yl]propan-1-ol(Compound 107)

In a 25-mL round-bottom flask was placed a solution of4-[3-(benzyloxy)propyl]-7-(1H-pyrazol-3-yl)quinolin-2-amine (180 mg,0.50 mmol, 1.00 equiv) in concentrated hydrogen chloride (5 mL). Theresulting solution was stirred for 5 hours at room temperature. Theresulting mixture was concentrated under vacuum. The pH of the solutionwas adjusted to 10 with NH₄OH. The resulting solution was extracted withDCM:MeOH (10:1, 5×10 mL) and the organic layers combined. The solutionwas dried over anhydrous sodium sulfate and concentrated under vacuum.The residue was purified by Prep-HPLC with the following conditions(HPLC-10): Column, X Bridge Shield RP18 OBD Column, 19*250 mm, 10 μm;mobile phase, Water (10 mmol/L NH₄HCO₃) and MeCN (5.0% MeCN up to 50.0%in 7 min); Detector, UV 254/210 nm. This resulted in 45 mg (29%) of3-[4-amino-7-(1H-pyrazol-3-yl)-[1,3]oxazolo[4,5-c]quinolin-2-yl]propan-1-olas a white solid. LC-MS: (ES, m/z): [M+H]⁺=269.3.

H-NMR: (DMSO-d₆, 300 MHz, ppm): δ 13.38-12.91 (m, 1H), 7.84-7.81 (m,2H), 7.67-7.64 (m, 2H), 6.78 (s, 1H), 6.58 (s, 1H), 6.30 (br s, 2H),4.60 (t, J=5.4 Hz, 2H), 3.54-3.49 (m, 2H), 2.91 (t, J=7.8 Hz, 2H),1.84-1.75 (m, 2H).

Example 5: Preparation ofN-[3-[2-amino-7-(1H-pyrazol-3-yl)quinolin-3-yl]propyl]-N-ethylacetamide(Compound 112)

Step 1: Synthesis of3-(3-chloropropyl)-7-(1H-pyrazol-3-yl)quinolin-2-amine

In a 100-mL round-bottom flask was placed a solution of3-[2-amino-7-(1H-pyrazol-3-yl)quinolin-3-yl]propan-1-ol (380 mg, 1.42mmol, 1.00 equiv) in dichloromethane (30 mL). To the solution was addedSO₂Cl₂ (15 mL). The resulting solution was stirred overnight at roomtemperature. The resulting mixture was concentrated under vacuum. Thisresulted in 574 mg (crude) of3-(3-chloropropyl)-7-(1H-pyrazol-3-yl)quinolin-2-amine as a yellowsolid. LC-MS: (ES, m/z): [M+H]⁺=287.1.

Step 2: Synthesis of3-[3-(ethylamino)propyl]-7-(1H-pyrazol-3-yl)quinolin-2-amine (Compound110)

In a 100-mL round-bottom flask, was placed a solution of3-(3-chloropropyl)-7-(1H-pyrazol-3-yl)quinolin-2-amine (574 mg, 2.00mmol, 1.00 equiv) in MeCN (20 mL). To the solution were added ethanamine(453 mg, 6.83 mmol, 5.00 equiv, 68%), potassium carbonate (554 mg, 4.01mmol, 2.00 equiv), and NaI (301 mg, 2.01 mmol, 1.00 equiv). Theresulting solution was stirred for 2 days at 70° C. in an oil bath. Theresulting mixture was concentrated under vacuum. The residue was appliedonto a silica gel column with dichloromethane/methanol (40:1). Thisresulted in 754 mg (crude) of3-[3-(ethylamino)propyl]-7-(1H-pyrazol-3-yl)quinolin-2-amine as a yellowsolid.

LC-MS: (ES, m/z): [M+H]⁺=296.2.

Step 3: Synthesis ofN-[3-[2-amino-7-(1H-pyrazol-3-yl)quinolin-3-yl]propyl]-N-ethylacetamide(Compound 112)

In a 100-mL round-bottom flask was placed a solution of3-[3-(ethylamino)propyl]-7-(1H-pyrazol-3-yl)quinolin-2-amine (400 mg,1.35 mmol, 1.00 equiv) and triethylamine (411 mg, 4.06 mmol, 3.00 equiv)in dichloromethane (20 mL). To the solution was added acetic anhydride(211 mg, 2.07 mmol, 1.50 equiv). The resulting solution was stirred for3 hours at room temperature. The resulting mixture was concentratedunder vacuum. The crude product was purified by Prep-HPLC with thefollowing conditions: Column, XBridge Shield RP18 OBD Column, 19*250 mm,10 μm; mobile phase, Water (10 mmol/L NH₄HCO₃) and MeCN (17.0% MeCN upto 55.0% in 8 min); Detector, UV 254/210 nm. This resulted in 30.9 mg(7%) ofN-[3-[2-amino-7-(1H-pyrazol-3-yl)quinolin-3-yl]propyl]-N-ethylacetamideas a white solid. H-NMR: ¹H NMR (300 MHz, DMSO-d₆) δ 13.38-12.90 (m,1H), 7.87-7.63 (m, 5H), 6.79 (s, 1H), 6.45-6.28 (m, 2H), 2.60-2.55 (m,6H), 2.00 (d, J=5.1 Hz, 3H), 1.87-1.82 (m, 2H), 1.13 (t, J=6.9 Hz, 2H),1.03 (t, J=6.9 Hz, 2H).LC-MS: (ES, m/z): [M+H]⁺=338.2.

Example II-1. Synthesis of 3-substituted Quinolines

Step 1. Preparation of2-amino-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzaldehyde

2-amino-4-bromobenzaldehyde (250 mg, 1.250 mmol),1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(521 mg, 1.875 mmol), and PdCl₂(dppf)-CH₂Cl₂ adduct (102 mg, 0.125 mmol)were placed in a vial. The vial was placed under vacuum and backfilledwith nitrogen. Tripotassium phosphate (2M aqueous) (1875 μl, 3.75 mmol)and dioxane (6249 μl) were added, nitrogen was bubbled through thesolution, and then the vial was capped and the reaction was heated to100° C. overnight. The reaction was cooled, diluted with water, andextracted three times with EtOAc. The organic layers were dried withsodium sulfate and concentrated. The residue was purified via ISCO (24 gcolumn; Hex/EtOAc; 0 to 50% gradient) to give2-amino-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzaldehyde(207 mg, 0.763 mmol, 61.0% yield).

Step 2. Preparation of3-(methoxymethyl)-7-(1H-pyrazol-5-yl)quinolin-2-amine. (Compound 113)

To a solution of 3-methoxypropanenitrile (12.55 mg, 0.147 mmol) and2-amino-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzaldehyde (20mg, 0.074 mmol) in DMSO (400 μl) was added KOtBu (16.54 mg, 0.147 mmol).The reaction was heated to 60° C. After 5 hours, the reaction wascomplete by LC/MS. The reaction was cooled, diluted with water, andextracted twice with EtOAc. The organic layers were concentrated. Theresidue was dissolved in 0.4 mL DCM and 0.4 mL TFA. After 2 hours, thereaction was complete by LC/MS. The reaction was concentrated andazeotroped with DCM. The residue was dissolved in DMF, filtered througha syringe filter, and purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 200 mm×19 mm, 5-μm particles; MobilePhase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; MobilePhase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient:a 0-minute hold at 7% B, 7-47% B over 20 minutes, then a 4-minute holdat 100% B; Flow Rate: 20 mL/min; Column Temperature: 25° C. Fractioncollection was triggered by MS signals. Fractions containing the desiredproduct were combined and dried via centrifugal evaporation. Thematerial was further purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 200 mm×19 mm, 5-μm particles; MobilePhase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; MobilePhase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid;Gradient: a 0-minute hold at 0% B, 0-40% B over 20 minutes, then a4-minute hold at 100% B; Flow Rate: 20 mL/min; Column Temperature: 25°C. Fraction collection was triggered by MS signals. Fractions containingthe desired product were combined and dried via centrifugal evaporationto give 3-(methoxymethyl)-7-(1H-pyrazol-5-yl)quinolin-2-amine (3.2 mg,16%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.33 (s, 1H), 8.06 (s, 1H), 7.98-7.88(m, 2H), 7.82 (s, 1H), 6.87 (d, J=1.5 Hz, 1H), 4.50 (s, 2H), 3.36 (s,3H). LC/MS conditions: Column: Waters XBridge C18, 2.1 mm×50 mm, 1.7 μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammoniumacetate; Temperature: 50° C.; Gradient: 0% B to 100% B over 3 min, thena 0.75 min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220nm). LC RT: 0.99 min. M/Z=255.2.

Unless otherwise specified, the same analytical LC/MS conditions appliedto the compounds characterized.

Compound 114 to Compound 122 were prepared according to syntheticprocedures similar to those described for Compound 113 from theappropriate starting materials.

Compd LC/MS RT ¹H NMR No. Structure [M + H]⁺ (min) (500 MHz, DMSO-d₆)114

336.2 0.96 δ 7.84 (s, 1H), 7.71 (br s, 2H), 7.65-7.55 (m, 2H), 6.76 (s,1H), 2.61-2.54 (m, 2H), 2.45- 2.26 (m, 6H), 1.82-1.70 (m, 2H), 1.57-1.45(m, 4H), 1.38 (br s, 2H) 115

310.1 1.44 δ 7.88 (s, 1H), 7.81 (s, 1H), 7.72 (br s, 1H), 7.68-7.60 (m,2H), 6.78 (s, 1H), 6.53 (br s, 1H), 3.60 (br s, 2H), 2.40 (br s, 4H) 4protons from morpholine are not visible in NMR. 116

295.0 1.12 δ 7.84 (s, 1H), 7.76 (s, 1H), 7.74-7.65 (m, 2H), 7.60 (br d,J = 7.9 Hz, 1H), 6.77 (s, 1H), 6.32 (br s, 1H), 4.03-3.89 (m, 2H), 2.91(br t, J = 11.3 Hz, 1H), 1.81 (br d, J = 13.1 Hz, 2H), 1.71-1.58 (m, 2H)one methylene of THP ring is not visible, likely due to overlap withsuppressed water peak. 117

324.2 1.24 δ 7.87 (s, 1H), 7.79 (s, 1H), 7.72-7.59 (m, 3H), 6.75 (d, J =1.9 Hz, 1H), 6.42 (br s, 1H), 3.91 (dt, J = 12.4, 6.2 Hz, 1H), 3.81-3.77(m, 1H), 3.77-3.70 (m, 1H), 3.64-3.57 (m, 1H), 2.59-2.56 (m, 1H),1.95-1.73 (m, 4H), 1.55-1.41 (m, 2H) 118

351.3 0.93 δ 8.38 (s, 1H), 8.11 (s, 1H), 7.98-7.89 (m, 2H), 7.86 (s,1H), 6.87 (d, J = 1.5 Hz, 1H), 4.02-3.86 (m, 1H), 3.26 (br s, 1H),2.80-2.70 (m, 6H), 2.06 (br d, J = 10.4 Hz, 2H), 1.83- 1.63 (m, 2H)several protons from piperidine ring are not visible, likely due tooverlap with water/DMSO. 119

308.2 0.99 δ 8.28 (s, 1H), 8.08 (s, 1H), 8.00-7.90 (m, 2H), 7.84 (br s,1H), 6.87 (d, J = 1.5 Hz, 1H), 4.43 (s, 2H), 3.49-3.37 (m, 2H) (overlapssuppressed water peak), 2.38 (br t, J = 8.1 Hz, 2H), 2.07-1.92 (m, 2H)120

280.9 1.14 δ 7.86 (s, 1H), 7.79 (s, 1H), 7.74-7.68 (m, 1H), 7.67-7.57(m, 2H), 6.78 (s, 1H), 6.20 (br s, 1H), 0.94 (br s, 2H), 0.72 (br s, 2H)Methylene adjacent to alcohol is not visible, possibly due to overlapwith suppressed water peak. 121

324.2 0.96 δ 8.30 (br s, 1H), 8.11 (br s, 1H), 7.98-7.81 (m, 3H), 6.86(s, 1H), 4.16-3.66 (m, 2H), 3.11 (br s, 1H). Peaks for morpholino ethylchain are broadened and have low integration 122

337.06 0.99 δ 7.84 (s, 1H), 7.76-7.68 (m, 2H), 7.65-7.57 (m, 2H), 6.76(d, J = 1.8 Hz, 1H), 2.78-2.69 (m, 2H), 2.60 (br t, J = 7.0 Hz, 2H),2.47-2.25 (m, 4H), 2.17 (s, 3H)

Step 2A. Alternative Procedure for Quinoline Formation: Preparation of3-(1H-imidazol-5-yl)-7-(1H-pyrazol-5-yl)quinolin-2-amine (Compound 123)

To a solution of 2-(1H-imidazol-5-yl)acetonitrile (11.84 mg, 0.111 mmol)and 2-amino-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzaldehyde(20 mg, 0.074 mmol) in EtOH (369 μl) was added sodium hydroxide (1M inEtOH) (14.74 μl, 0.015 mmol). The reaction was heated to 70° C. After 1hour, 75 μL of 1M sodium hydroxide in EtOH was added, and heating wascontinued overnight. LC/MS showed that the reaction was complete. Thereaction was cooled and concentrated. The residue was dissolved in 0.4mL DCM and 0.4 mL TFA was added. After 45 minutes, LC/MS showed that thereaction was complete. The reaction was concentrated and azeotroped withDCM. The residue was dissolved in DMF, filtered through a syringefilter, and the crude material was purified via preparative LC/MS withthe following conditions: Column: XBridge C18, 200 mm×19 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM. ammnoniumacetate; Gradient: a 0-minute hold at 0% B, 0-40% B over minutes, then a4-minute hold at 100% B; Flow Rate: 20 mL/min; Column Temperature: 25°C. Fraction collection was triggered by MS and UV signals. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to give3-(1H-imidazol-5-yl)-7-(1H-pyrazol-5-yl)quinolin-2-amine (6.4 mg, 31%).¹H NMR (500 MHz, DMSO-d₆) δ 8.27 (s, 1H), 7.86 (d, J=8.3 Hz, 2H), 7.81(s, 1H), 7.73-7.59 (m, 3H), 6.77 (d, J=1.8 Hz, 1H). LC RT: 0.86 min.M/Z=277.2.

Compound 124 to Compound 127 were prepared according to the syntheticprocedures described for Compound 123 from the appropriate startingmaterials.

Compd. LC/MS RT ¹H NMR No. Structure [M + H]⁺ (min) (500 MHz, DMSO-d₆)124

331.1 1.19 δ 8.90 (s, 1H), 8.56 (s, 1H), 8.34 (br d, J = 4.5 Hz, 1H),8.15 (br d, J = 7.7 Hz, 1H), 7.91 (s, 1H), 7.84-7.79 (m, 1H), 7.75 (brs, 1H), 7.42 (dd, J = 8.1, 4.7 Hz, 1H), 6.93-6.75 (m, 2H) 125

318.1 1.10 δ 8.48 (s, 1H), 8.01-7.95 (m, 1H), 7.91 (br d, J = 4.8 Hz,2H), 7.80 (d, J = 8.3 Hz, 1H), 7.73 (s, 1H), 7.68 (br d, J = 8.4 Hz,1H), 7.48 (br d, J = 7.5 Hz, 2H), 6.81 (d, J = 1.9 Hz, 1H), 4.67 (br s,2H) 126

292.1 0.95 δ 8.77 (br s, 1H), 7.96-7.52 (m, 5H), 6.84 (br s, 1H), 2.48(br s, 3H) 127

326.9 1.36 δ 8.33 (s, 1H), 8.23-8.14 (m, 2H), 7.98 (br d, J = 7.6 Hz,3H), 7.87 (br s, 1H), 7.73 (d, J = 8.5 Hz, 1H), 7.50 (br d, J = 8.5 Hz,1H), 6.89 (s, 1H)

Example II-2: Synthesis of 4-amino Substituted Quinolines

Step 1. Preparation of 7-bromo-4-chloroquinoline

To a suspension of 7-bromoquinolin-4-ol (2.5 g, 11.16 mmol) in toluene(20 mL) was added POCl₃ (2.080 mL, 22.32 mmol). The reaction was heatedto 100° C. After 1.5 hours, the reaction was cooled, and then ice wasadded. The reaction was stirred vigorously for ca. 30 min, then waterwas added. The reaction was extracted twice with DCM. The organic layerswere washed with saturated aqueous NaHCO₃ and brine, then dried oversodium sulfate and concentrated. LC/MS shows that some product remainsin the initial aqueous layer. The aqueous layer was stirred andsaturated aqueous NaHCO₃ solution was added carefully. The precipitatedsolid was filtered off, washed with water, and dried. Material fromorganic layer and the filtered solid were combined and dried under highvacuum to give 7-bromo-4-chloroquinoline (2.46 g, 10.14 mmol, 91%yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.80 (d, J=4.7 Hz, 1H), 8.33(d, J=1.9 Hz, 1H), 8.12 (d, J=9.0 Hz, 1H), 7.75 (dd, J=9.0, 2.0 Hz, 1H),7.52 (d, J=4.8 Hz, 1H).

Step 2. Preparation of 7-bromo-4-chloroquinoline 1-oxide

To a solution of 7-bromo-4-chloroquinoline (2.0 g, 8.25 mmol) in DCM(55.0 ml) was added mCPBA (6.10 g, 24.74 mmol). The reaction was stirredovernight, then quenched with saturated sodium thiosulfate solution. Thereaction was stirred for 0.5 hours, then saturated aqueous sodiumbicarbonate was added. The reaction was extracted twice with DCM. Theorganic layers were washed with brine, dried with sodium sulfate, andconcentrated to give 7-bromo-4-chloroquinoline 1-oxide (2.16 g, 8.36mmol, quantitative yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.99 (d,J=1.9 Hz, 1H), 8.43 (d, J=6.6 Hz, 1H), 8.10 (d, J=9.0 Hz, 1H), 7.86 (dd,J=9.0, 2.0 Hz, 1H), 7.40 (d, J=6.6 Hz, 1H).

Step 3. Preparation of 7-bromo-4-chloroquinolin-2-amine

In one round-bottomed flask, 7-bromo-4-chloroquinoline 1-oxide (9400 mg,36.4 mmol) was suspended in DCM (150 mL). Ts-Cl (7626 mg, 40.0 mmol) wasadded. This mixture was stirred for one hour. In a second round-bottomedflask, ammonium chloride (9725 mg, 182 mmol) (dried in an oven at 110°C. overnight) was suspended in DCM (150 mL). Triethylamine (25.3 mL, 182mmol) was added and the mixture was stirred for 0.5 hours, then thecontents of the first roundbottom flask were added to the second. Thereaction was stirred overnight, then filtered and concentrated. Theresidue was dissolved in 100 ml of hot DCM. The solution was cooled toroom temperature and the solid was filtered off. The filter cake waswashed with 100 mL of −20° C. DCM. The filter cake was suspended inwater (50 mL) and filtered. The solid is the desired product7-bromo-4-chloroquinolin-2-amine. The DCM filtrate was evaporated,suspended in water (100 mL), and filtered. The filter cake was washedwith 100 mL of −20° C. DCM to give additional product. The combinedsolids were dried under high vacuum to give7-bromo-4-chloroquinolin-2-amine (6.52 g, 69.6%). ¹H NMR (400 MHz,DMSO-d₆) δ 7.79 (d, J=8.7 Hz, 1H), 7.65 (d, J=1.9 Hz, 1H), 7.39 (dd,J=8.8, 2.0 Hz, 1H), 6.98 (s, 1H), 6.88 (s, 2H).

Step 4. Preparation of4-chloro-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)quinolin-2-amine

In each of two 40 mL pressure vials was placed(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)boronic acid (0.714 g,3.64 mmol), 7-bromo-4-chloroquinolin-2-amine (0.750 g, 2.91 mmol), andPdCl₂(dppf)-DCM adduct (0.238 g, 0.291 mmol). The vials were placedunder vacuum and backfilled with nitrogen three times. Dioxane (14.56ml) and tripotassium phosphate (2M aqueous) (4.37 ml, 8.74 mmol) wereadded to each vial, nitrogen was bubbled through the solution, then thereaction was heated to 100° C. overnight. The vials were cooled, dilutedwith EtOAc and water, and combined. The reaction was extracted threetimes with EtOAc, and then the organic layers were washed with brine,dried with sodium sulfate, and concentrated. The residue was purifiedvia ISCO (80 g column; DCM/MeOH; 0 to 10% gradient) to give4-chloro-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)quinolin-2-amine(1.14 g, 59.5% yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.11 (d, J=8.6Hz, 1H), 7.82 (d, J=1.4 Hz, 1H), 7.65 (d, J=1.5 Hz, 1H), 7.52 (dd,J=8.5, 1.7 Hz, 1H), 6.90 (s, 1H), 6.45 (d, J=1.8 Hz, 1H), 5.38-5.26 (m,1H), 4.90 (br s, 1H), 4.22-4.09 (m, 2H), 3.65 (td, J=11.7, 2.3 Hz, 1H),2.68-2.51 (m, 1H), 2.14-1.51 (m, 5H).

Step 5: Preparation ofN4-((1H-pyrazol-3-yl)methyl)-7-(1H-pyrazol-5-yl)quinoline-2,4-diamine(Compound 128)

To a solution of4-chloro-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)quinolin-2-amine(20 mg, 0.061 mmol) and (1H-pyrazol-3-yl)methanamine (59.1 mg, 0.608mmol) in DMSO (0.5 mL) was added Hunig's Base (0.032 mL, 0.182 mmol).The reaction was heated to 120° C. overnight. The reaction was cooled,diluted with water, and extracted three times with EtOAc. The organiclayers were concentrated, then dissolved in 0.4 mL DCM and 0.4 mL TFA.After 1 hour, the reaction was complete by LCMS. The reaction wasconcentrated and azeotroped with DCM. The residue was dissolved in DMF,filtered through a syringe filter, and the crude material was purifiedvia preparative LC/MS with the following conditions: Column: XBridgeC18, 200 mm×19 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: a 0-minutehold at 0% B, 0-40% B over 20 minutes, then a 4-minute hold at 100% B;Flow Rate: 20 mL/min; Column Temperature: 25° C. Fraction collection wastriggered by MS signals. Fractions containing the desired product werecombined and dried via centrifugal evaporation. The material was furtherpurified via preparative LC/MS with the following conditions: Column:XBridge C18, 200 mm×19 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: a 3-minutehold at 0% B, 0-32% B over 25 minutes, then a 5-minute hold at 100% B;Flow Rate: 20 mL/min; Column Temperature: 25° C. Fraction collection wastriggered by MS signals. Fractions containing the desired product werecombined and dried via centrifugal evaporation to giveN4-((1H-pyrazol-3-yl)methyl)-7-(1H-pyrazol-5-yl)quinoline-2,4-diamine(4.6 mg, 24.7%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.00 (br d, J=8.2 Hz, 1H),7.75 (s, 1H), 7.72 (br s, 1H), 7.58 (br s, 1H), 7.54 (br d, J=7.9 Hz,1H), 7.43 (br s, 1H), 6.76 (s, 1H), 6.62-6.41 (m, 1H), 6.20 (s, 1H),5.76 (s, 1H), 4.42 (br d, J=5.2 Hz, 2H).

LC RT: 0.99 min. M/Z=306.18.

Step 5b: Procedure for use of amine salts. Preparation ofN4-(1-(6-methoxypyridin-2-yl)ethyl)-7-(1H-pyrazol-5-yl)quinoline-2,4-diamine,7 TFA (Compound 129)

To a solution of4-chloro-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)quinolin-2-amine(20 mg, 0.061 mmol) and 1-(6-methoxypyridin-2-yl)ethan-1-amine, HCl (115mg, 0.608 mmol) in DMSO (0.5 mL) was added Hunig's Base (0.159 mL, 0.912mmol). The reaction was heated to 100° C. overnight. Then, the reactiontemperature was increased to 120° C. for 5.5 hours. The reaction wascooled, diluted with water, and extracted three times with EtOAc. Theorganic layers were concentrated. The residue was dissolved in 0.4 mLDCM and 0.4 mL TFA. After ca. 1 hour, the reaction was complete by LCMS.The reaction was concentrated and azeotroped with DCM. The residue wasdissolved in DMF, filtered through a syringe filter, and the crudematerial was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 200 mm×19 mm, 5-μm particles; MobilePhase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; MobilePhase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid;Gradient: a 0-minute hold at 9% B, 9-46% B over 23 minutes, then a6-minute hold at 100% B; Flow Rate: 20 mL/min; Column Temperature: 25°C. Fraction collection was triggered by MS signals. Fractions containingthe desired product were combined and dried via centrifugal evaporationto giveN4-(1-(6-methoxypyridin-2-yl)ethyl)-7-(1H-pyrazol-5-yl)quinoline-2,4-diamine,2 TFA (4.4 mg, 12%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.51 (br d, J=8.5 Hz,1H), 8.18 (br d, J=6.4 Hz, 1H), 8.01-7.81 (m, 3H), 7.68 (br t, J=N7.6Hz, 1H), 7.58 (br s, 2H), 6.96 (br d, J=7.3 Hz, 1H), 6.86 (br s, 1H),6.71 (br d, J=7.9 Hz, 1H), 5.63 (s, 1H), 4.70 (br t, J=6.6 Hz, 1H), 3.88(s, 3H), 1.68 (br d, J=6.7 Hz, 3H). LC/MS conditions: Column: WatersXBridge C18, 2.1 mm×50 mm, 1.7 μm particles; Mobile Phase A: 5:95acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10 mM ammonium acetate; Temperature: 50° C.;Gradient: 0% B to 100% B over 3 min, then a 0.50 min hold at 100% B;Flow: 1 mL/min; Detection: MS and UV (220 nm). LC RT: 1.46 min.M/Z=361.31.

Compound 130 to Compound 166, Compound 222 to Compound 290 and Compound351 were prepared according to the synthetic procedures described forCompound 129 from the appropriate starting materials.

Compd. LC/MS RT ¹H NMR No. Structure [M + H]⁺ (min) (500 MHz, DMSO-d₆)130

309.2  1.21 δ 7.81 (s, 1H), 7.76-7.67 (m, 2H), 7.58 (br d, J = 8.2 Hz,1H), 6.75 (s, 1H), 6.31 (br s, 1H), 6.24 (s, 1H), 3.08 (br s, 4H), 2.60(br s, 4H), 2.29 (s, 3H) 131

296.3  1.12 δ 8.11 (br s, 1H), 8.02 (br s, 1H), 7.96-7.90 (m, 1H), 7.89-7.80 (m, 2H), 6.81 (d, J = 2.0 Hz, 2H), 6.34 (s, 2H), 3.88 (m, 4H),3.36-3.29 (m, 2H) 2 protons from morpholine ring are not visible, likelydue to overlap with water/water suppression. 132

311.9  1.05 δ 7.89 (br d, J = 8.5 Hz, 1H), 7.76-7.66 (m, 2H), 7.51 (brs, 1H), 6.81 (br d, J = 4.0 Hz, 1H), 6.75 (s, 1H), 6.32-6.11 (m, 1H),5.70 (s, 1H), 3.25 (br s, 1H), 1.80 (br t, J = 7.5 Hz, 2H), 1.20 (s, 6H)One proton from sidechain is missing in NMR, likely due to overlap withsuppressed water peak. 133

284.3  0.69 δ 8.04 (br d, J = 8.6 Hz, 1H), 7.80 (br s, 1H), 7.72 (br s,1H), 7.67-7.56 (m, 1H), 6.76 (s, 1H), 5.80 (s, 1H), 4.04-3.95 (m, 1H),3.89 (s, 2H), 1.18 (d, J = 6.1 Hz, 3H) 134

283.9  1.09 δ 8.26 (d, J = 8.7 Hz, 1H), 8.00- 7.91 (m, 2H), 7.88-7.78(m, 2H), 7.47 (br s, 2H), 6.83 (d, J = 2.1 Hz, 1H), 5.89 (s, 1H),4.05-3.98 (m, 1H), 3.89 (s, 2H), 1.18 (d, J = 6.2 Hz, 3H) 135

317.0  1.06 δ 8.56 (br d, J = 4.3 Hz, 1H), 8.07 (br d, J = 8.5 Hz, 1H),7.81- 7.68 (m, 4H), 7.65-7.56 (m, 1H), 7.33 (br d, J = 7.6 Hz, 1H),7.31-7.24 (m, 1H), 6.78 (s, 1H), 5.59 (s, 1H), 4.55 (br d, J = 5.5 Hz,2H) 136

284.3  0.99 δ 8.02 (br d, J = 8.5 Hz, 1H), 7.84 (s, 1H), 7.74 (br s,1H), 7.61 (br d, J = 4.9 Hz, 1H), 6.78 (s, 1H), 6.59 (br d, J = 12.2 Hz,1H), 6.20 (s, 1H), 3.74 (br s, 2H), 2.91 (s, 3H). One methylene fromsidechain is not visible, likely due to overlap with suppressed waterpeak. 137

323.9  1.13 δ 8.15 (br d, J = 8.5 Hz, 1H), 7.91-7.68 (m, 4H), 6.83 (s,1H), 5.80 (s, 1H), 3.86 (br d, J = 10.7 Hz, 2H), 3.68-3.53 (m, 2H), 3.28(br t, J = 11.6 Hz, 2H), 1.98 (br s, 1H), 1.66 (br d, J = 12.2 Hz, 2H),1.33-1.19 (m, 2H) 138

325.1  1.08 δ 8.16 (br d, J = 8.5 Hz, 1H), 8.01-7.74 (m, 4H), 7.49-7.29(m, 1H), 6.84 (br s, 1H), 5.82 (s, 1H), 3.36 (br s, 2H), 2.98 (s, 3H),2.85 (s, 3H), 2.76 (br t, J = 6.9 Hz, 2H) 139

311.2  1.03 δ 7.91 (br d, J = 8.5 Hz, 2H), 7.78-7.66 (m, 2H), 7.51 (brd, J = 7.6 Hz, 1H), 6.85 (br s, 1H), 6.75 (s, 1H), 6.36 (br s, 1H), 5.73(s, 1H), 2.60 (br d, J = 4.3 Hz, 3H) methylenes of sidechains are notvisible in NMR, likely due to overlap with suppressed water peak. 140

332.2  0.87 δ 8.25-8.09 (m, 2H), 7.99 (br s, 1H), 7.88 (br s, 2H), 7.75(br s, 2H), 6.86 (br s, 1H), 5.87 (s, 1H), 3.76 (br d, J = 5.5 Hz, 2H),3.56 (br t, J = 6.3 Hz, 2H), 3.10 (s, 3H) 141

296.2  1.06 δ 8.01 (br d, J = 8.5 Hz, 1H), 7.77 (s, 1H), 7.73 (br s,1H), 7.56 (br d, J = 7.9 Hz, 1H), 6.76 (s, 1H), 6.60 (br d, J = 17.4 Hz,1H), 6.45 (br s, 1H), 5.82 (s, 1H), 3.13 (br d, J = 5.2 Hz, 2H), 1.22(s, 6H) 142

296.0  0.75 δ 8.28 (br d, J = 8.5 Hz, 1H), 7.97 (br s, 1H), 7.88 (br s,1H), 7.79 (br d, J = 8.5 Hz, 1H), 7.53 (br s, 2H), 6.83 (br s, 1H), 5.82(s, 1H), 4.46 (br s, 1H), 4.02- 3.94 (m, 1H), 3.94-3.84 (m, 1H),3.77-3.67 (m, 1H), 3.54 (br d, J = 10.7 Hz, 1H), 2.12- 1.93 (m, 2H) 143

296.3  1.05 δ 8.06 (br d, J = 8.5 Hz, 1H), 7.81 (br s, 1H), 7.75 (br s,1H), 7.55 (br d, J = 3.1 Hz, 1H), 6.76 (s, 1H), 6.48 (br d, J = 5.5 Hz,1H), 5.83 (s, 1H), 4.41 (br s, 1H), 3.85 (br dd, J = 10.1, 4.0 Hz, 1H),3.75 (br d, J = 7.6 Hz, 1H), 2.12-1.99 (m, 1H), 1.97- 1.91 (m, 1H) Twoprotons from pyrrolidine ring are not visible, likely due to overlapwith suppressed water peak. 144

298.1  1.07 δ 8.23 (br d, J = 8.2 Hz, 1H), 8.12 (br s, 1H), 7.96 (br s,1H), 7.89-7.78 (m, 2H), 7.62 (br s, 2H), 6.85 (br s, 1H), 5.80 (s, 1H),3.47 (br d, J = 4.9 Hz, 1H), 3.28 (br d, J = 10.4 Hz, 1H), 1.76-1.67 (m,2H), 1.60-1.46 (m, 2H). Two protons from sidechain are not visible,likely due to low integration or overlap with suppressed water peak. 145

310.2  1.07 δ 8.14-7.97 (m, 2H), 7.91- 7.80 (m, 3H), 6.83 (br s, 1H),3.87-3.77 (m, 1H), 3.55 (br d, J = 8.5 Hz, 1H), 3.13 (br t, J = 11.4 Hz,1H), 2.98-2.87 (m, 1H), 1.96 (br s, 2H), 1.67 (br d, J = 8.5 Hz, 2H).One proton from piperidine is missing, likely due to overlap withsuppressed water peak or low integration. 146

373.2  1.21 δ 8.76 (br s, 1H), 8.12 (br d, J = 7.3 Hz, 1H), 7.96-7.71(m, 7H), 7.57-7.41 (m, 5H), 6.83 (br s, 1H), 5.85 (s, 1H), 3.61 (br d, J= 5.2 Hz, 2H), 3.48 (br d, J = 4.3 Hz, 1H). one proton from sidechain ismissing, likely due to overlap with suppressed water peak or lowintegration. 147

296.3  1.07 δ 8.04 (br d, J = 8.5 Hz, 1H), 7.79 (br s, 1H), 7.77-7.69(m, 1H), 7.61 (br s, 1H), 6.78 (br s, 1H), 5.79 (s, 1H), 2.99 (s, 1H),0.66 (br s, 2H), 0.61 (br s, 2H). One proton from sidechain is notvisible, possibly due to overlap with suppressed water peak or lowintegration. 148

317.3  0.92 δ 8.50 (br d, J = 4.6 Hz, 2H), 8.04 (br d, J = 8.5 Hz, 1H),7.79- 7.65 (m, 3H), 7.59 (br d, J = 6.7 Hz, 1H), 7.35 (br d, J = 4.6 Hz,2H), 6.78 (s, 1H), 4.51 (br d, J = 5.5 Hz, 2H) 149

318.3  1.01 δ 9.20 (br s, 1H), 8.88 (br s, 1H), 8.29 (br d, J = 8.2 Hz,1H), 7.98-7.79 (m, 4H), 7.74-7.64 (m, 4H), 6.86 (br s, 1H), 5.75 (s,1H), 4.87 (br d, J = 5.8 Hz, 2H) 150

317.3  1.11 δ 12.50 (br s, 1H), 8.78 (br s, 1H), 8.66 (br s, 1H), 8.53(br s, 1H), 8.26 (br d, J = 8.5 Hz, 1H), 7.94 (s, 1H), 7.90-7.79 (m,3H), 7.65 (br s, 2H), 7.50-7.43 (m, 1H), 6.86 (s, 1H), 5.74 (s, 1H),4.62 (br d, J = 5.2 Hz, 2H) 151

331.2  1.06 δ 12.50 (br s, 1H), 8.62 (br d, J = 4.9 Hz, 1H), 8.20 (br s,1H), 8.15 (br d, J = 8.5 Hz, 1H), 7.99- 7.90 (m, 2H), 7.86-7.79 (m, 2H),7.69 (br s, 2H), 7.54 (br d, J = 7.6 Hz, 1H), 7.48-7.40 (m, 1H), 6.84(s, 1H), 5.89 (s, 1H), 3.71 (br d, J = 6.1 Hz, 1H), 3.23 (br t, J = 7.0Hz, 1H). Two protons are missing from sidechain, either due to overlapwith suppressed water peak or low integration. 152

320.3  0.77 δ 8.68-8.53 (m, 1H), 8.11- 7.98 (m, 2H), 7.90 (br s, 1H),7.85-7.76 (m, 2H), 7.56 (br s, 2H), 7.39 (br s, 1H), 6.85 (s, 1H), 5.78(s, 1H), 4.43 (br s, 2H), 2.94-2.83 (m, 1H) One proton from sidechain ismissing, likely due to low integration or overlap with suppressed waterpeak. 153

300.3  0.64 δ 7.92 (br d, J = 8.2 Hz, 1H), 7.73 (br s, 2H), 7.52 (br s,1H), 6.76 (s, 1H), 6.65 (br s, 1H), 6.24-6.10 (m, 1H), 5.74 (s, 1H),3.85-3.77 (m, 1H), 3.33- 3.26 (m, 1H), 3.14-3.05 (m, 2H). One protonfrom sidechain is not visible, likely due to overlap with water peak.154

347.1  1.06 δ 8.64 (br s, 1H), 8.49 (br s, 1H), 8.20 (br d, J = 7.6 Hz,2H), 7.96-7.79 (m, 4H), 7.61 (br s, 2H), 7.46-7.34 (m, 1H), 6.85 (s,1H), 5.92 (s, 1H), 4.99 (br s, 1H). The sidechain methylene is notvisible in the NMR, likely due to overlap with the suppressed waterpeak. 155

347.0  1.05 δ 8.55 (br d, J = 4.0 Hz, 1H), 8.00 (br d, J = 8.5 Hz, 1H),7.87- 7.80 (m, 1H), 7.79 (br s, 1H), 7.74 (br s, 1H), 7.60 (br d, J =7.6 Hz, 2H), 7.34-7.25 (m, 1H), 7.11 (br s, 1H), 6.79 (s, 2H), 5.83 (s,1H), 4.98 (br dd, J = 8.1, 3.5 Hz, 1H), 3.68-3.58 (m, 1H), 3.49-3.30 (m,1H) 156

337.2  0.92 δ 8.74 (br s, 1H), 8.27 (br d, J = 8.5 Hz, 1H), 7.97 (br s,1H), 7.87 (br s, 2H), 7.62 (br s, 2H), 7.33 (s, 1H), 6.86 (br s, 1H),5.82 (s, 1H), 4.59 (br d, J = 5.5 Hz, 2H), 2.65 (s, 3H) 157

324.0  0.96 δ 8.35 (br d, J = 7.6 Hz, 1H), 8.01-7.90 (m, 1H), 7.88-7.74(m, 2H), 7.57 (br s, 2H), 7.27 (br d, J = 6.7 Hz, 1H), 6.85 (br s, 1H),5.87 (s, 1H), 4.99 (br d, J = 3.4 Hz, 1H), 4.05 (br s, 1H), 3.55-3.33(m, 1H), 1.96-1.29 (m, 8H) 158

337.3  0.74 δ 8.21 (br d, J = 5.2 Hz, 1H), 8.08 (br d, J = 7.9 Hz, 1H),7.91- 7.72 (m, 2H), 7.68-7.54 (m, 1H), 6.78 (br s, 1H), 6.75-6.55 (m,1H), 5.84 (br s, 1H), 4.34 (br s, 1H), 3.89 (br s, 1H), 3.79- 3.57 (m,1H), 2.18 (br d, J = 6.1 Hz, 1H), 1.95 (br d, J = 5.5 Hz, 1H), 1.82 (s,3H) Two protons from pyrrolidine ring are not visible, due to overlapwith suppressed water peak or low integration. 159

306.1  0.66 δ 8.81 (br s, 1H), 8.56 (br s, 1H), 8.22 (br d, J = 8.2 Hz,1H), 7.96 (br s, 1H), 7.91-7.82 (m, 2H), 7.75 (br s, 2H), 7.55 (br s,1H), 6.86 (s, 1H), 5.83 (s, 1H), 4.60 (br d, J = 4.3 Hz, 1H) One protonfrom methylene is not visible, likely due to overlap with suppressedwater peak or low integration. 160

324.1  0.97 δ 8.33 (br d, J = 8.5 Hz, 1H), 7.98-7.90 (m, 1H), 7.90-7.75(m, 2H), 7.65 (br d, J = 7.6 Hz, 1H), 7.49 (br s, 2H), 6.85 (br s, 1H),5.91 (s, 1H), 4.97 (br d, J = 4.9 Hz, 1H), 3.60 (br d, J = 4.6 Hz, 1H),3.46-3.22 (m, 2H), 2.03-1.92 (m, 2H), 1.71 (br d, J = 5.2 Hz, 2H), 1.43-1.19 (m, 4H) 161

367.2  1.20 δ 8.75 (br d, J = 4.3 Hz, 1H), 8.29-8.22 (m, 2H), 8.01 (brt, J = 7.6 Hz, 1H), 7.95 (br s, 1H), 7.88-7.79 (m, 2H), 7.75 (d, J = 7.9Hz, 1H), 7.69 (br s, 1H), 7.63-7.57 (m, 1H), 6.83 (d, J = 1.8 Hz, 1H),6.07 (s, 1H), 4.27 (td, J = 14.9, 6.1 Hz, 2H) 162

324.3  1.11 δ 8.23 (br d, J = 8.2 Hz, 1H), 7.92-7.69 (m, 3H), 7.40-7.04(m, 2H), 6.82 (br s, 1H), 5.87 (s, 1H), 3.65-3.53 (m, 1H), 3.31-3.19 (m,1H), 1.96 (br s, 2H), 1.70 (br s, 3H), 1.41-1.18 (m, 6H) 163

321.3  0.93 δ 8.49 (s, 1H), 8.03-7.89 (m, 2H), 7.82 (br s, 1H), 7.76 (brs, 1H), 7.66 (br d, J = 7.0 Hz, 1H), 7.43 (br s, 1H), 6.98-6.83 (m, 1H),6.80 (s, 1H), 5.75 (s, 1H), 4.50 (br t, J = 5.6 Hz, 2H), 3.68 (br d, J =4.9 Hz, 1H) One proton from sidechain is not visible, likely due to lowintegration or overlap with suppressed water peak. 164

343.2  1.20 δ 8.43 (br d, J = 4.0 Hz, 1H), 7.95 (br s, 1H), 7.90 (br d,J = 8.5 Hz, 1H), 7.80 (br s, 2H), 7.64 (br d, J = 7.6 Hz, 1H), 7.27 (brdd, J = 7.5, 4.7 Hz, 1H), 6.82 (s, 1H), 6.38 (s, 1H), 4.49 (br s, 2H),3.21 (br s, 2H), 3.16 (s, 2H) 165

284.0  0.94 δ 8.29 (br d, J = 8.5 Hz, 1H), 7.90 (br s, 1H), 7.80 (br d,J = 7.1 Hz, 2H), 7.40 (br s, 1H), 7.30 (br s, 1H), 6.82 (d, J = 1.9 Hz,1H), 5.90 (s, 1H), 3.76- 3.67 (m, 1H), 3.65-3.50 (m, 2H), 1.27 (d, J =6.5 Hz, 3H) 166

254.4  1.02 δ 8.05 (br d, J = 8.5 Hz, 1H), 7.95 (br s, 1H), 7.87-7.65(m, 4H), 6.83 (s, 1H), 6.04 (s, 1H), 3.15 (s, 6H) 222

292.9  0.79 δ 8.23 (br d, J = 8.2 Hz, 1H), 8.12-8.05 (m, 1H), 7.96 (brs, 1H), 7.91-7.81 (m, 1H), 7.57 (br dd, J = 5.3, 4.1 Hz, 2H), 6.91- 6.83(m, 1H), 5.81 (s, 1H), 3.44-3.33 (m, 2H), 2.65 (br t, J = 6.9 Hz, 2H),2.03-1.94 (m, 2H) 223

360.3  0.84 δ 8.21 (br d, J = 8.2 Hz, 1H), 8.02-7.95 (m, 1H), 7.93-7.84(m, 3H), 7.83-7.69 (m, 2H), 6.86 (s, 1H), 6.05 (s, 1H), 3.71 (br d, J =6.4 Hz, 2H), 3.05 (s, 3H), 1.40 (s, 6H) 224

321.0  0.66 δ 8.24-8.11 (m, 2H), 7.94 (br s, 1H), 7.83 (br d, J = 9.2Hz, 2H), 7.72 (br s, 1H), 6.84 (d, J = 2.1 Hz, 1H), 5.87 (s, 1H),3.72-3.61 (m, 2H), 3.15-3.06 (m, 2H) 225

320.1  0.71 δ 8.86 (s, 1H), 8.22-8.10 (m, 2H), 7.95 (br s, 1H), 7.83 (brd, J = 8.5 Hz, 2H), 7.78 (br s, 2H), 7.46 (s, 1H), 6.84 (d, J = 2.2 Hz,1H), 5.89 (s, 1H), 3.66-3.56 (m, 2H), 3.06 (t, J = 6.8 Hz, 2H) 226

307.1  0.71 δ 8.74-8.61 (m, 1H), 8.21 (br d, J = 8.2 Hz, 1H), 7.99-7.90(m, 1H), 7.89-7.77 (m, 3H), 7.65 (br s, 2H), 6.85 (br s, 1H), 5.86 (s,1H), 4.63 (br d, J = 5.2 Hz, 2H) 227

307.0  0.92 δ 8.73 (br s, 1H), 8.55 (br s, 1H), 8.25 (br d, J = 7.6 Hz,1H), 8.03-7.92 (m, 1H), 7.87 (br s, 2H), 7.73-7.57 (m, 2H), 6.86 (br s,1H), 5.88 (br s, 1H), 4.76- 4.50 (m, 2H) 228

306.1  0.76 δ 7.98 (d, J = 8.9 Hz, 1H), 7.76 (s, 1H), 7.72 (br s, 1H),7.60 (br s, 2H), 7.56 (br d, J = 7.6 Hz, 1H), 7.44-7.34 (m, 1H), 6.78(d, J = 1.8 Hz, 1H), 6.69-6.51 (m, 1H), 5.79 (s, 1H), 4.31 (br d, J =5.5 Hz, 2H) 229

320.1  1.00 δ 8.62 (br s, 1H), 8.23 (d, J = 8.8 Hz, 1H), 7.98-7.92 (m,1H), 7.84 (br d, J = 8.2 Hz, 2H), 7.63 (d, J = 1.8 Hz, 1H), 7.58 (br d,J = 1.6 Hz, 1H), 6.85 (d, J = 1.9 Hz, 1H), 6.21 (d, J = 2.2 Hz, 1H),5.86 (s, 1H), 4.46 (d, J = 6.0 Hz, 2H), 3.80 (s, 3H) 230

307.2  0.98 δ 12.74 (s, 1H), 8.64 (br t, J = 5.0 Hz, 1H), 8.37 (s, 1H),8.22 (d, J = 8.5 Hz, 1H), 7.96 (s, 1H), 7.88-7.75 (m, 4H), 7.23 (s, 1H),6.85 (d, J = 2.1 Hz, 1H), 5.92 (s, 1H), 4.64 (br d, J = 5.2 Hz, 2H) 231

335.3  0.97 δ 8.55 (s, 1H), 8.28-8.18 (m, 1H), 8.11-8.04 (m, 1H), 8.00(s, 1H), 7.95 (br t, J = 5.1 Hz, 1H), 7.85 (br d, J = 8.7 Hz, 2H), 7.63(br d, J = 1.3 Hz, 2H), 6.86 (d, J = 1.9 Hz, 1H), 5.76 (s, 1H), 4.34 (t,J = 6.9 Hz, 2H), 3.29 (q, J = 6.1 Hz, 1H), 2.28-2.18 (m, 2H). One protonis not visible in NMR, likely due to overlap with suppressed water peak.232

310.3  1.08 δ 12.46 (br s, 1H), 8.31 (br d, J = 8.8 Hz, 1H), 7.93 (br d,J = 4.0 Hz, 1H), 7.87-7.80 (m, 2H), 7.67-7.57 (m, 2H), 7.42 (br d, J =6.4 Hz, 1H), 6.85 (d, J = 2.3 Hz, 1H), 5.90 (s, 1H), 4.31- 4.23 (m, 1H),3.77-3.67 (m, 1H), 2.09-1.98 (m, 1H), 1.95- 1.76 (m, 3H), 1.72-1.64 (m,1H), 1.60-1.49 (m, 1H) 233

296.0  0.74 δ 8.07 (d, J = 8.8 Hz, 1H), 7.81- 7.69 (m, 2H), 7.57 (br d,J = 7.6 Hz, 1H), 7.09-6.94 (m, 1H), 6.78 (d, J = 1.8 Hz, 1H), 5.51 (s,1H), 4.36 (br t, J = 6.5 Hz, 1H), 4.04-3.91 (m, 1H), 2.43-2.32 (m, 2H),2.30-2.20 (m, 2H) 234

296.0  0.73 δ 8.05 (d, J = 8.5 Hz, 1H), 7.77- 7.73 (m, 1H), 7.73-7.68(m, 1H), 7.54 (br d, J = 8.2 Hz, 1H), 7.03-6.93 (m, 1H), 6.77 (d, J =1.8 Hz, 1H), 6.57-6.43 (m, 1H), 5.61 (s, 1H), 3.99-3.88 (m, 1H),2.80-2.71 (m, 2H), 1.96-1.87 (m, 2H) One proton is not visible in NMR,likely due to overlap with suppressed water peak. 235

310.3  1.13 δ 8.31 (br d, J = 7.9 Hz, 2H), 7.93 (br s, 1H), 7.84 (br d,J = 8.5 Hz, 2H), 7.57 (br s, 2H), 7.41 (br d, J = 6.7 Hz, 1H), 6.85 (d,J = 1.8 Hz, 1H), 5.90 (s, 1H), 4.28 (br s, 1H), 3.78-3.67 (m, 1H),2.09-1.98 (m, 1H), 1.95- 1.76 (m, 3H), 1.75-1.63 (m, 1H), 1.61-1.48 (m,1H) 236

335.0  1.00 δ 8.20-8.13 (m, 1H), 8.11 (br d, J = 8.8 Hz, 1H), 8.00-7.92(m, 1H), 7.90-7.78 (m, 3H), 7.72-7.62 (m, 2H), 6.85 (d, J = 1.9 Hz, 1H),5.81 (s, 1H), 4.64 (t, J = 6.1 Hz, 2H), 3.80- 3.73 (m, 2H), 2.21 (s, 3H)237

320.0  0.95 δ 8.01 (br d, J = 8.5 Hz, 1H), 7.80-7.75 (m, 1H), 7.73 (brs, 1H), 7.54 (br d, J = 8.2 Hz, 1H), 7.45 (s, 1H), 7.30-7.16 (m, 1H),6.77 (d, J = 1.9 Hz, 1H), 5.78 (s, 2H), 4.26 (br d, J = 4.8 Hz, 1H),2.19 (s, 3H) 238

345.3  1.14 δ 12.46 (s, 1H), 8.72-8.65 (m, 1H), 8.60 (br d, J = 5.0 Hz,1H), 8.21 (d, J = 8.6 Hz, 1H), 8.17- 8.07 (m, 2H), 7.93 (d, J = 1.4 Hz,1H), 7.87-7.80 (m, 2H), 7.73- 7.58 (m, 3H), 6.85 (d, J = 2.2 Hz, 1H),5.80 (s, 1H), 3.39-3.28 (m, 2H), 2.87-2.80 (m, 2H), 2.10-1.98 (m, 2H)239

351.0  1.09 δ 12.42 (s, 1H), 8.83 (s, 1H), 8.21 (br t, J = 5.6 Hz, 1H),8.15 (d, J = 8.7 Hz, 1H), 7.93 (s, 1H), 7.87-7.81 (m, 2H), 7.69-7.59 (m,1H), 6.85 (d, J = 2.3 Hz, 1H), 5.82 (s, 1H), 3.21-3.13 (m, 2H), 2.30 (s,3H) Two protons are not visible in NMR, likely due to overlap withsuppressed water peak. 240

306.0  0.94 δ 8.73 (br t, J = 5.6 Hz, 1H), 8.42- 8.29 (m, 1H), 8.21 (d,J = 8.7 Hz, 1H), 7.98 (s, 1H), 7.94- 7.82 (m, 4H), 7.58 (s, 2H), 6.87(d, J = 2.3 Hz, 1H), 5.70 (s, 1H), 4.89 (d, J = 5.5 Hz, 2H) 241

334.0  0.99 δ 8.72 (br s, 1H), 8.21 (br d, J = 8.6 Hz, 1H), 8.08-8.01(m, 1H), 7.98-7.91 (m, 1H), 7.85 (br d, J = 8.4 Hz, 2H), 7.70- 7.60 (m,3H), 7.47 (s, 1H), 6.86 (d, J = 1.9 Hz, 1H), 5.77 (s, 1H), 4.27 (br t, J= 6.9 Hz, 2H), 3.35- 3.25 (m, 1H), 2.23 (quin, J = 6.9 Hz, 2H) Oneproton is not visible in NMR, likely due to overlap with suppressedwater peak. 242

320.3  1.00 δ 8.69-8.59 (m, 1H), 8.27 (br d, J = 8.1 Hz, 1H), 8.01-7.93(m, 1H), 7.86 (br d, J = 7.6 Hz, 2H), 7.77-7.61 (m, 2H), 7.35 (s, 1H),6.86 (s, 1H), 6.27 (s, 1H), 5.82 (s, 1H), 4.61 (br d, J = 5.3 Hz, 2H),3.87 (s, 3H) 243

320.1  0.87 δ 8.61 (br d, J = 4.6 Hz, 1H), 8.52 (br s, 1H), 8.23 (br d,J = 8.5 Hz, 1H), 7.97 (br s, 1H), 7.87 (br d, J = 8.9 Hz, 2H), 7.79 (brd, J = 1.3 Hz, 2H), 7.45 (br s, 1H), 6.86 (s, 1H), 5.85 (s, 1H), 4.55(br d, J = 4.4 Hz, 2H), 3.76 (s, 3H) 244

323.2  0.88 δ 9.03 (s, 1H), 8.78 (br s, 1H), 8.18 (br d, J = 8.4 Hz,1H), 7.94 (br d, J = 9.5 Hz, 2H), 7.90- 7.80 (m, 2H), 7.75-7.60 (m, 1H),6.86 (br s, 1H), 5.88 (br s, 1H), 4.81 (br d, J = 4.5 Hz, 2H) 245

310.0  0.89 δ 8.05 (br d, J = 8.4 Hz, 1H), 7.81-7.76 (m, 1H), 7.75-7.70(m, 1H), 7.63-7.54 (m, 1H), 6.96-6.84 (m, 1H), 6.80 (br s, 1H), 5.72 (s,1H), 4.23-4.13 (m, 1H), 2.35-2.24 (m, 1H), 2.08-1.96 (m, 1H), 1.81 (brs, 1H), 1.81-1.70 (m, 1H), 1.70- 1.57 (m, 2H) One proton is not visiblein NMR, likely due to overlap with suppressed water peak. 246

310.0  0.89 δ 8.32 (br d, J = 8.4 Hz, 1H), 7.97-7.89 (m, 1H), 7.87-7.79(m, 2H), 7.76 (br d, J = 6.3 Hz, 1H), 7.68-7.54 (m, 2H), 6.85 (s, 1H),5.85 (s, 1H), 4.35-4.24 (m, 1H), 4.12-4.03 (m, 1H), 2.30-2.18 (m, 1H),2.10-2.00 (m, 1H), 1.99-1.82 (m, 2H), 1.74-1.61 (m, 1H), 1.61-1.51 (m,1H) 247

310.1  0.83 δ 8.02 (d, J = 8.5 Hz, 1H), 7.78- 7.75 (m, 1H), 7.74-7.68(m, 1H), 7.60-7.50 (m, 1H), 6.81- 6.72 (m, 2H), 5.72 (s, 1H), 4.22- 4.14(m, 1H), 3.86-3.78 (m, 1H), 2.30 (dt, J = 13.8, 7.0 Hz, 1H), 2.07-1.96(m, 1H), 1.84- 1.71 (m, 2H), 1.70-1.56 (m, 2H) 248

310.2  0.89 δ 8.13 (d, J = 8.5 Hz, 1H), 7.79 (s, 1H), 7.76-7.71 (m, 1H),7.67 (br d, J = 7.9 Hz, 1H), 7.17 (br dd, J = 7.9, 5.2 Hz, 1H), 6.82 (d,J = 1.8 Hz, 1H), 5.78 (s, 1H), 4.32-4.23 (m, 1H), 4.05 (br d, J = 6.4Hz, 1H), 2.27-2.20 (m, 1H), 2.05-1.91 (m, 2H), 1.88- 1.82 (m, 1H),1.64-1.49 (m, 2H) 249

307.2  0.86 δ 8.05 (s, 1H), 7.97 (d, J = 8.5 Hz, 1H), 7.75 (s, 1H), 7.71(br s, 1H), 7.55 (br d, J = 7.3 Hz, 2H), 7.18 (s, 1H), 6.77 (d, J = 1.8Hz, 1H), 6.31 (br s, 1H), 5.74 (s, 1H), 4.56 (br d, J = 5.5 Hz, 2H) 250

324.1  0.94 δ 8.00 (d, J = 8.9 Hz, 1H), 7.77 (s, 1H), 7.73 (br s, 1H),7.59- 7.51 (m, 1H), 6.76 (d, J = 1.8 Hz, 1H), 6.71-6.56 (m, 1H), 6.16(br d, J = 3.7 Hz, 1H), 5.77 (s, 1H), 4.02 (br s, 1H), 1.85-1.65 (m,4H), 1.64-1.47 (m, 2H), 1.44-1.30 (m, 2H) One proton is not visible inNMR, likely due to overlap with suppressed water peak. 251

324.1  1.13 δ 8.35 (br d, J = 8.5 Hz, 1H), 7.94 (br s, 1H), 7.89-7.79(m, 2H), 7.71 (br s, 2H), 7.27 (br d, J = 7.0 Hz, 1H), 6.84 (s, 1H),5.89 (s, 1H), 4.05 (br s, 1H), 3.56-3.47 (m, 1H), 1.95-1.47 (m, 6H),1.42-1.30 (m, 2H) 252

320.2  0.82 δ 8.87 (s, 1H), 8.51 (br t, J = 4.9 Hz, 1H), 8.23 (d, J =8.5 Hz, 1H), 7.96 (br s, 1H), 7.89-7.75 (m, 4H), 7.60 (s, 1H), 6.86 (d,J = 2.4 Hz, 1H), 5.91 (s, 1H), 4.66 (br d, J = 4.6 Hz, 2H), 3.86 (s, 3H)253

240.2  0.72 δ 8.10 (d, J = 8.8 Hz, 1H), 8.06- 7.98 (m, 1H), 7.95-7.74(m, 3H), 7.48-7.30 (m, 1H), 6.83 (s, 1H), 5.70 (s, 1H), 2.91 (d, J = 4.6Hz, 3H) 254

314.1  0.73 δ 7.97 (d, J = 8.5 Hz, 1H), 7.80- 7.75 (m, 1H), 7.73 (br s,1H), 7.59-7.52 (m, 1H), 6.82 (br d, J = 2.1 Hz, 1H), 6.77 (d, J = 1.8Hz, 1H), 6.62-6.47 (m, 1H), 5.74 (s, 1H), 4.01-3.90 (m, 1H), 3.38 (br d,J = 5.2 Hz, 1H), 3.29 (s, 3H), 3.28-3.21 (m, 1H), 3.18-3.10 (m, 1H) Oneproton is not visible in NMR, likely due to overlap with suppressedwater peak. 255

284.0  0.89 δ 8.26-8.21 (m, 1H), 8.13 (br t, J = 5.3 Hz, 1H), 7.94 (brs, 1H), 7.84 (br d, J = 7.3 Hz, 2H), 7.58 (br s, 1H), 6.85 (d, J = 2.1Hz, 1H), 5.85 (s, 1H), 3.62 (t, J = 5.5 Hz, 2H) Five protons are notvisible in NMR, likely due to overlap with suppressed water peak 256

316.2  1.10 δ 8.11-8.05 (m, 1H), 7.78 (s, 1H), 7.74 (br s, 1H), 7.67 (brs, 1H), 7.59 (br d, J = 8.5 Hz, 1H), 7.41-7.33 (m, 5H), 7.31-7.12 (m,1H), 6.78 (d, J = 1.8 Hz, 1H), 6.49 (br s, 2H), 5.62 (s, 1H), 4.49 (brd, J = 5.9 Hz, 2H) 257

409.2  1.10 δ 8.83-8.75 (m, 1H), 8.29 (br d, J = 8.4 Hz, 1H), 7.96 (brs, 1H), 7.90 (br d, J = 8.1 Hz, 2H), 7.59 (br s, 2H), 7.47-7.26 (m, 2H),7.26-7.16 (m, 1H), 7.12 (br d, J = 7.4 Hz, 2H), 6.88 (s, 1H), 5.68 (s,1H), 4.57 (br d, J = 5.6 Hz, 2H), 2.96 (s, 3H) 258

409.1  0.92 δ 8.13-8.03 (m, 1H), 7.79 (s, 2H), 7.77-7.70 (m, 1H), 7.70-7.49 (m, 1H), 7.35 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.5 Hz, 2H), 6.81(d, J = 1.8 Hz, 1H), 6.77- 6.63 (m, 1H), 5.64 (s, 1H), 4.44 (br d, J =5.8 Hz, 2H), 2.96 (s, 3H) 259

346.1  1.17 δ 8.83-8.60 (m, 1H), 8.26 (br d, J = 8.5 Hz, 1H), 7.85 (brs, 2H), 7.50 (br s, 1H), 7.27 (t, J = 8.1 Hz, 1H), 6.95-6.90 (m, 2H),6.89-6.80 (m, 2H), 5.69 (s, 1H), 4.52 (br d, J = 5.8 Hz, 2H), 3.72 (s,3H) 260

334.1  1.19 δ 8.90-8.75 (m, 1H), 8.33- 8.24 (m, 1H), 8.00-7.95 (m, 1H),7.89 (br d, J = 8.9 Hz, 2H), 7.61 (br s, 2H), 7.53-7.35 (m, 2H),7.27-7.17 (m, 2H), 7.12 (br t, J = 9.0 Hz, 1H), 6.88 (s, 1H), 5.70 (s,1H), 4.60 (br d, J = 5.8 Hz, 2H) 261

320.1  1.06 δ 8.21 (br d, J = 6.7 Hz, 2H), 7.85 (br d, J = 2.0 Hz, 2H),7.68 (br s, 2H), 7.57 (s, 1H), 6.90- 6.85 (m, 1H), 6.20 (s, 1H), 5.88(s, 1H), 3.01 (br t, J = 7.5 Hz, 2H). One methylene is not visible,possibly due to overlap with suppressed water peak. 262

320.3  1.03 δ 8.13 (br d, J = 7.2 Hz, 1H), 8.01-7.90 (m, 1H), 7.85 (brd, J = 9.3 Hz, 1H), 7.80-7.70 (m, 1H), 7.70-7.59 (m, 1H), 7.59- 7.40 (m,1H), 6.86 (d, J = 2.1 Hz, 1H), 6.23 (t, J = 1.6 Hz, 1H), 5.76 (s, 1H),3.59-3.49 (m, 4H) 263

320.1  0.90 δ 8.24 (br d, J = 8.9 Hz, 1H), 8.03 (s, 1H), 7.87 (br s,2H), 7.83 (br d, J = 8.5 Hz, 1H), 7.77 (br s, 1H), 6.85 (br s, 1H),6.35- 6.24 (m, 1H), 6.21 (s, 1H), 4.62 (br s, 2H), 3.01 (br s, 3H) 264

331.0  0.96 δ 8.52-8.48 (m, 1H), 8.48- 8.46 (m, 1H), 7.85-7.79 (m, 2H),7.79-7.66 (m, 2H), 7.66- 7.50 (m, 1H), 7.40 (dd, J = 7.6, 4.6 Hz, 1H),6.76 (d, J = 2.1 Hz, 1H), 6.77-6.71 (m, 1H), 6.26 (br s, 1H), 6.24-6.20(m, 1H), 4.42 (s, 2H), 2.76 (s, 3H) 265

310.2  1.08 δ 7.80 (d, J = 1.2 Hz, 1H), 7.76 (s, 1H), 7.71 (br s, 1H),7.56 (br d, J = 8.2 Hz, 1H), 6.76 (d, J = 2.1 Hz, 1H), 6.30-6.19 (m,2H), 3.88-3.76 (m, 4H), 3.45-3.34 (m, 2H), 2.06 (quin, J = 5.6 Hz, 2H).One proton from sidechain is missing in NMR, likely due to overlap withsuppressed water peak. 266

326.2  0.88 δ 8.08-7.98 (m, 1H), 7.83- 7.71 (m, 2H), 7.57 (br d, J = 8.4Hz, 1H), 7.13-7.00 (m, 1H), 6.84-6.76 (m, 1H), 6.73-6.58 (m, 1H), 5.75(s, 1H), 3.85 (br d, J = 9.6 Hz, 2H), 3.81-3.74 (m, 1H), 3.72-3.55 (m,2H), 3.41-3.29 (m, 1H), 3.26-3.20 (m, 1H). One proton from sidechain ismissing in NMR, likely due to overlap with suppressed water peak. 267

325.1  0.58 δ 8.32-8.20 (m, 1H), 8.17 (br t, J = 5.5 Hz, 1H), 7.97 (brs, 1H), 7.86 (br d, J = 8.2 Hz, 2H), 7.78 (br s, 2H), 6.86 (d, J = 1.2Hz, 1H), 5.91 (s, 1H), 4.02 (br dd, J = 12.1, 3.2 Hz, 2H), 3.80-3.69 (m,1H), 3.46-3.33 (m, 1H), 3.29-3.13 (m, 1H), 3.10-3.00 (m, 1H), 2.94-2.89(m, 1H) One proton from sidechain is missing in NMR, likely due tooverlap with suppressed water peak. 268

325.1  0.68 δ 8.20 (d, J = 8.9 Hz, 1H), 7.98- 7.92 (m, 1H), 7.91-7.82(m, 2H), 7.78-7.69 (m, 1H), 6.87 (d, J = 1.8 Hz, 1H), 5.90 (s, 1H),4.03-3.93 (m, 1H), 3.86-3.78 (m, 1H), 3.16-3.07 (m, 1H), 3.03-2.95 (m,1H). A number of the protons from sidechain is missing in NMR, likelydue to overlap with suppressed water peak. 269

325.1  0.92 δ 8.18 (d, J = 8.8 Hz, 1H), 8.13- 8.06 (m, 1H), 7.97 (s,1H), 7.92- 7.87 (m, 1H), 7.85 (br s, 1H), 7.79 (br s, 2H), 6.87 (d, J =2.1 Hz, 1H), 5.92 (s, 1H), 4.06 (br dd, J = 11.9, 2.1 Hz, 1H), 3.97-3.89 (m, 1H), 3.78-3.53 (m, 2H), 3.52-3.41 (m, 1H), 3.34 (br d, J = 13.1Hz, 1H), 3.16- 3.07 (m, 1H), 2.97-2.86 (m, 1H) 270

381.1  1.21 δ 13.27-13.10 (m, 1H), 12.69- 12.60 (m, 1H), 8.34 (br d, J =5.0 Hz, 1H), 8.30 (br d, J = 8.5 Hz, 1H), 7.96 (br s, 1H), 7.89-7.83 (m,2H), 7.76-7.75 (m, 1H), 7.81-7.73 (m, 1H), 6.86 (d, J = 1.7 Hz, 1H),5.59 (s, 1H), 4.40-4.32 (m, 1H), 4.29-4.22 (m, 2H), 3.99 (br dd, J =8.4, 4.8 Hz, 2H), 1.40 (s, 9H). One extra proton likely due to TFA salt.271

301.9  1.10 δ 13.25-13.12 (m, 1H), 8.01- 7.95 (m, 1H), 7.90-7.87 (m,1H), 7.86-7.77 (m, 4H), 6.84 (d, J = 1.9 Hz, 1H), 5.65 (s, 1H), 4.96 (brt, J = 11.8 Hz, 4H) 272

310.2  1.02^(a) δ 8.02-7.96 (m, 1H), 7.81 (s, 1H), 7.78-7.72 (m, 1H),7.63- 7.55 (m, 1H), 6.77 (d, J = 1.7 Hz, 1H), 6.67-6.50 (m, 2H), 6.08-6.00 (m, 1H), 4.88-4.77 (m, 1H), 4.09-4.02 (m, 1H), 3.88- 3.80 (m, 2H),2.21-2.13 (m, 1H), 2.03-1.92 (m, 2H), 1.90 (s, 2H), 1.79-1.70 (m, 1H)273

280.2  1.17^(a) δ 8.16-8.11 (m, 1H), 7.82- 7.79 (m, 1H), 7.78-7.73 (m,1H), 7.68-7.62 (m, 1H), 7.46- 7.37 (m, 1H), 6.99-6.83 (m, 1H), 6.80 (d,J = 1.7 Hz, 1H), 5.66-5.63 (m, 1H), 4.01-3.95 (m, 1H), 2.45-2.38 (m,2H), 2.15-2.06 (m, 2H), 1.88 (s, 2H), 1.84-1.75 (m, 2H) 274

324.1  0.96 δ 7.85-7.81 (m, 1H), 7.75- 7.73 (m, 1H), 7.72 (s, 1H), 7.63-7.55 (m, 1H), 6.76 (d, J = 1.7 Hz, 1H), 6.43-6.33 (m, 2H), 6.23 (s, 1H),4.65-4.52 (m, 1H), 2.69 (br t, J = 10.3 Hz, 1H), 1.98-1.91 (m, 1H), 1.90(s, 1H), 1.84-1.74 (m, 3H), 1.21- 1.12 (m, 1H). Several protons frompiperidine ring are not visible, likely due to overlap with water/DMSO.275

296.1  0.97 δ 8.17-8.09 (m, 1H), 7.82- 7.80 (m, 1H), 7.78-7.72 (m, 1H),7.62-7.53 (m, 1H), 6.81- 6.74 (m, 1H), 5.79-5.69 (m, 1H), 4.16-4.05 (m,1H), 4.00- 3.95 (m, 2H), 3.94-3.85 (m, 2H), 2.34-2.21 (m, 1H), 2.19 2.03(m, 1H) 276

296.4  0.96 δ 8.27-8.22 (m, 1H), 7.90- 7.87 (m, 1H), 7.87-7.85 (m, 1H),7.80-7.77 (m, 1H), 6.92- 6.81 (m, 1H), 5.93-5.86 (m, 1H), 4.39-4.29 (m,1H), 4.11- 4.03 (m, 2H), 3.99-3.88 (m, 2H), 2.51-2.40 (m, 1H), 2.22-2.13 (m, 1H) 277

296.2  0.98 δ 8.39-8.29 (m, 1H), 7.98- 7.91 (m, 1H), 7.89-7.74 (m, 2H),6.93-6.82 (m, 1H), 5.87- 5.78 (m, 1H), 4.25-4.14 (m, 1H), 4.01-3.88 (m,2H), 3.88- 3.74 (m, 2H), 2.35-2.25 (m, 1H), 2.20-2.04 (m, 1H) 278

310.2  0.87 δ 8.40-8.25 (m, 2H), 8.02- 7.93 (m, 1H), 7.88-7.81 (m, 1H),6.91-6.80 (m, 1H), 6.01- 5.90 (m, 1H), 3.79-3.64 (m, 1H), 3.57-3.36 (m,2H), 2.93- 2.91 (m, 2H), 2.00-1.90 (m, 2H), 1.81-1.64 (m, 2H) 279

310.4  0.75 δ 8.29-8.15 (m, 1H), 7.94- 7.85 (m, 2H), 7.82-7.76 (m, 1H),7.39-7.31 (m, 1H), 6.87- 6.82 (m, 1H), 4.14-4.05 (m, 1H), 3.64-3.54 (m,2H), 3.51- 3.41 (m, 2H), 1.99-1.71 (m, 4H) 280

282.0  0.75 δ 8.13-8.03 (m, 1H), 7.80- 7.74 (m, 1H), 7.63-7.54 (m, 1H),7.39-7.28 (m, 1H), 6.84- 6.75 (m, 1H), 6.26-6.09 (m, 1H), 5.48-5.41 (m,1H), 4.96- 4.87 (m, 2H), 4.71-4.58 (m, 2H) 281

308.0  1.32 δ 8.40-8.24 (m, 1H), 7.98- 7.92 (m, 1H), 7.89-7.80 (m, 1H),7.76-7.65 (m, 1H), 6.93- 6.81 (m, 1H), 5.94-5.83 (m, 1H), 3.03-2.85 (m,3H), 2.06- 1.95 (m, 2H), 1.87-1.76 (m, 2H), 1.51-1.29 (m, 4H) 282

323.9  1.02 δ 8.37-8.25 (m, 1H), 7.93- 7.78 (m, 1H), 7.74-7.67 (m, 1H),7.66-7.58 (m, 1H), 7.43- 7.32 (m, 1H), 7.30-7.21 (m, 1H), 5.92-5.84 (m,1H), 2.99- 2.84 (m, 1H), 2.52-2.51 (m, 1H), 2.41-2.32 (m, 1H), 2.12-1.86 (m, 1H), 1.61-1.43 (m, 1H), 1.37-1.22 (m, 1H), 1.19- 1.12 (m, 2H)283

324.0  1.02 δ 8.35-8.23 (m, 1H), 7.78- 7.65 (m, 1H), 7.73-7.65 (m, 1H),7.63-7.55 (m, 1H), 7.39- 7.32 (m, 1H), 7.30-7.20 (m, 1H), 5.91-5.83 (m,1H), 3.47- 3.27 (m, 1H), 2.58-2.54 (m, 1H), 2.54-2.47 (m, 1H), 2.41-2.33 (m, 1H), 2.13-1.90 (m, 1H), 1.60-1.42 (m, 1H), 1.38- 1.21 (m, 1H),1.17-1.11 (m, 2H) 284

 0.99 331.2 δ 8.59 (br s, 1H), 8.50 (br d, J = 3.1 Hz, 1H), 8.24-8.12(m, 2H), 7.94 (s, 1H), 7.88-7.80 (m, 3H), 7.71-7.60 (m, 2H), 7.45 (dd, J= 7.6, 5.2 Hz, 1H), 6.85 (d, J = 2.1 Hz, 1H), 5.89 (s, 1H), 3.62-3.38(m, 2H), 3.04 (br t, J = 7.5 Hz, 2H) 285

309.2  0.86 δ 13.22-13.17 (m, 1H), 8.20- 8.12 (m, 1H), 8.11-8.02 (m,1H), 8.01-7.92 (m, 1H), 7.91- 7.82 (m, 2H), 7.80-7.64 (m, 2H), 6.86 (d,J = 1.9 Hz, 1H), 5.93-5.81 (m, 1H), 3.92-3.83 (m, 2H), 3.31-3.25 (m,1H), 3.25-3.18 (m, 1H), 3.17-3.14 (m, 1H), 2.21-2.11 (m, 1H), 2.04-1.90(m, 2H), 1.75-1.67 (m, 1H) 286

309.2  0.61 δ 7.82-7.76 (m, 2H), 7.72 (br s, 1H), 7.55 (br d, J = 7.9Hz, 1H), 6.76 (d, J = 1.5 Hz, 1H), 6.23 (s, 1H), 6.19 (s, 1H), 3.44-3.32 (m, 2H), 3.08-2.95 (m, 4H), 1.94 (br d, J = 4.6 Hz, 2H). Two of thediazepine protons are not observed likely due to overlap with the H₂Osuppression. 287

300.3  0.72 δ 8.11 (br d, J = 8.5 Hz, 1H), 7.90-7.82 (m, 1H), 7.80-7.66(m, 2H), 7.62-7.45 (m, 1H), 7.24-7.03 (m, 1H), 6.82 (s, 1H), 5.81 (s,1H), 3.86-3.79 (m, 1H), 3.66-3.53 (m, 1H), 3.49-3.32 (m, 2H), 3.25-3.16(m, 1H) 288

310.1  1.13 δ 8.34-8.26 (m, 1H), 7.96- 7.90 (m, 1H), 7.88-7.81 (m, 2H),7.62-7.58 (m, 1H), 6.90- 6.77 (m, 1H), 6.04-5.92 (m, 1H), 4.02-3.90 (m,1H), 3.86- 3.78 (m, 1H), 3.67-3.63 (m, 1H), 3.46-3.25 (m, 2H), 2.16-2.03 (m, 1H), 1.83-1.71 (m, 2H), 1.71-1.57 (m, 1H) 289

310.2  1.05 δ 8.39-8.23 (m, 1H), 8.01- 7.92 (m, 1H), 7.93-7.79 (m, 2H),7.63-7.59 (m, 1H), 6.90- 6.82 (m, 1H), 6.03-5.92 (m, 1H), 4.03-3.93 (m,1H), 3.88- 3.77 (m, 1H), 3.46-3.33 (m, 2H), 2.20-2.02 (m, 1H), 1.86-1.72 (m, 2H), 1.72-1.55 (m, 1H) 290

342.4  0.95 δ 8.17-8.16 (m, 1H), 8.16- 8.14 (m, 1H), 8.11-8.09 (m, 1H),7.89-7.85 (m, 2H), 7.80- 7.78 (m, 1H), 3.86-3.76 (m, 1H), 3.74-3.61 (m,1H), 2.38- 2.27 (m, 1H), 2.11-1.86 (m, 4H), 1.67-1.32 (m, 4H) 291

340.4  0.90 δ 8.43-8.33 (m, 1H), 8.00- 7.93 (m, 1H), 7.93-7.89 (m, 1H),7.88-7.82 (m, 2H), 6.89- 6.81 (m, 1H), 5.94-5.85 (m, 1H), 4.20-4.10 (m,2H), 4.10- 4.03 (m, 1H), 4.00-3.92 (m, 1H), 3.88-3.80 (m, 1H), 3.80-3.64 (m, 2H), 1.20-1.12 (m, 3H) 351

310.3  0.84 δ 8.32-8.19 (m, 1H), 8.17- 8.05 (m, 1H), 7.99-7.91 (m, 1H),7.62-7.41 (m, 1H), 6.92- 6.80 (m, 1H), 5.91-5.81 (m, 1H), 3.86-3.77 (m,1H), 3.76- 3.71 (m, 1H), 3.71-3.63 (m, 1H), 3.59-3.44 (m, 1H), 3.32-3.23 (m, 2H), 2.75-2.61 (m, 1H), 2.14-1.96 (m, 1H), 1.74- 1.58 (m, 1H)aLC/MS conditions: Column: Waters XBridge C18, 2.1 mm x 50 mm, 1.7 μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 0.1%trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1%trifluoroacetic acid; Temperature: 50° C.; Gradient: 0% B to 100% B over3 min, then a 0.50 min hold at 100% B; Flow: 1 mL/min; Detection: MS andUV (220 nm).

Example II-3: Synthesis of4-(1H-imidazol-1-yl)-7-(1H-pyrazol-5-yl)quinolin-2-amine (Compound 167)

To a solution of 1H-imidazole (45.6 mg, 0.669 mmol) and4-chloro-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)quinolin-2-amine(22 mg, 0.067 mmol) in NMP (446 μl) was added potassium tert-butoxide(18.77 mg, 0.167 mmol). The reaction was heated to 100° C. overnight.The reaction was diluted with water and extracted twice with EtOAc. Theorganic layers were concentrated. The residue was dissolved in 0.4 mLDCM and 0.4 mL TFA. After 1 hour, the reaction was concentrated andazeotroped with DCM. The reaction was dissolved in DMF, filtered througha syringe filter, and The crude material was purified via preparativeLC/MS with the following conditions: Column: XBridge C18, 200 mm×19 mm,5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mMammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mMammonium acetate; Gradient: a 0-minute hold at 2% B, 2-42% B overminutes, then a 4-minute hold at 100% B; Flow Rate: 20 mL/min; ColumnTemperature: 25° C. Fraction collection was triggered by MS and UVsignals. Fractions containing the desired product were combined anddried via centrifugal evaporation to give (1.8 mg, 9.5%). ¹H NMR (500MHz, DMSO-d₆) δ 8.50-8.28 (m, 1H), 8.10 (br s, 1H), 7.95-7.75 (m, 3H),7.57 (br d, J=8.2 Hz, 1H), 7.40 (br s, 1H), 7.00-6.80 (m, 2H). LC/MSConditions: Column: Waters XBridge C18, 2.1 mm×50 mm, 1.7 μm particles;Mobile Phase A: 5:95. acetonitrile:water with 10 mM ammonium acetate;Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate;Temperature: 50° C.; Gradient: 0% B to 100% B over 3 min, then a 0.75min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). LCRT: 0.89 min. M/Z=277.4.

Example II-4: Synthesis of 4-Substituted Quinolines from an UnprotectedIntermediate

Step 1: Preparation of 4-chloro-7-(1H-pyrazol-5-yl)quinolin-2-amine

4-Chloro-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)quinolin-2-amine(100 mg, 0.304 mmol) was dissolved in DCM (1.5 mL) and TFA (1.5 mL).After 1 hour, the reaction was complete by LC/MS. The reaction wasconcentrated and azeotroped with DCM. The residue was dissolved in asmall amount of DCM, and then saturated sodium bicarbonate solution wasadded. The precipitated solid was filtered, washed with water, anddried. The solid was suspended in saturated sodium bicarbonate solution,stirred for 15 minutes, then filtered and washed twice with water togive 4-chloro-7-(1H-pyrazol-5-yl)quinolin-2-amine (66 mg, 0.270 mmol,89% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 7.93-7.86 (m, 2H), 7.84-7.72 (m,2H), 6.91 (s, 1H), 6.84 (d, J=2.1 Hz, 1H), 6.64 (br s, 2H).

Step 2: Preparation ofN4-(3-(dimethylamino)propyl)-7-(1H-pyrazol-5-yl)quinoline-2,4-diamine, 2TFA (Compound 168)

N1,N1-Dimethylpropane-1,3-diamine (104 mg, 1.022 mmol) in DMA (681 μl)was added Hunig's Base (53.5 μl, 0.307 mmol). The reaction was heated to120° C. overnight, then the reaction was heated to 150° C. for a further24 hours. The reaction was cooled, quenched with AcOH, diluted withMeOH, filtered through a syringe filter, and the crude material waspurified via preparative LC/MS with the following conditions: Column:XBridge C18, 200 mm×19 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: a 3-minutehold at 0% B, 0-40% B over minutes, then a 4-minute hold at 100% B; FlowRate: 20 mL/min; Column Temperature: 25° C. Fraction collection wastriggered by MS and UV signals. Fractions containing the desired productwere combined and dried via centrifugal evaporation to giveN4-(3-(dimethylamino)propyl)-7-(1H-pyrazol-5-yl)quinoline-2,4-diamine, 2TFA (12.2 mg, 22.1%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.21 (br d, J=8.5 Hz,1H), 8.09 (br s, 1H), 7.95 (br s, 1H), 7.85 (br d, J=7.9 Hz, 2H), 7.78(br s, 2H), 6.85 (s, 1H), 5.85 (s, 1H), 3.44-3.33 (m, 1H), 3.23-3.13 (m,2H), 2.80 (s, 6H), 2.11-1.98 (m, 2H). Note: one proton from methylene ofsidechain is missing, likely due to overlap with suppressed water peak.Column: Waters XBridge C18, 2.1 mm×50 mm, 1.7 μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50°C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B;Flow: 1 mL/min; Detection: MS and UV (220 nm). LC RT: 0.90 min.M/Z=311.1.

Compound 169 to Compound 171 were prepared according to the syntheticprocedures described for Compound 168 from the appropriate startingmaterials.

Compd. LC/MS RT ¹H NMR No. Structure [M + H]⁺ (min) (500 MHz, DMSO-d₆)169

270.0 1.11 δ 8.03 (br d, J = 8.5 Hz, 1H), 7.80 (s, 1H), 7.74 (br s, 1H),7.66 (br d, J = 7.6 Hz, 1H), 7.28 (br s, 1H), 6.83 (s, 1H), 5.76 (s,1H), 3.67 (br t, J = 5.8 Hz, 2H), 3.36-3.27 (m, 2H) 170

325.1 1.05 δ 8.17 (br d, J = 8.5 Hz, 1H), 8.07-8.01 (m, 1H), 7.97 (br s,1H), 7.90-7.73 (m, 3H), 6.83 (d, J = 1.9 Hz, 1H), 5.95 (s, 1H), 3.71 (brd, J = 5.2 Hz, 2H), 1.29- 1.19 (m, 6H). Several protons from aminosidechain are missing, likely due to overlap with suppressed water peak.171

284.0 0.81 δ 7.97 (br d, J = 8.5 Hz, 1H), 7.77 (s, 1H), 7.73 (br s, 1H),7.55 (br d, J = 7.9 Hz, 1H), 6.96 (br s, 1H), 6.77 (s, 1H), 5.71 (s,1H), 3.55 (br t, J = 6.1 Hz, 1H), 3.25 (br d, J = 5.8 Hz, 2H), 1.85-1.78 (m, 2H). One proton from alcohol sidechain is missing, likely dueto overlap with suppressed water peak.

Example 5: Synthesis of a 4-ether Substituted Quinoline from anUnprotected Intermediate

Step 1: Synthesis of4-((2-amino-7-(1H-pyrazol-5-yl)quinolin-4-yl)oxy)butan-1-ol, TFA(Compound 172)

To a solution of 4-chloro-7-(1H-pyrazol-5-yl)quinolin-2-amine (22 mg,0.090 mmol) and butane-1,4-diol (81 mg, 0.899 mmol) in DMSO (599 μl) wasadded potassium tert-butoxide (20.18 mg, 0.180 mmol). The reaction washeated to 100° C. overnight, then potassium tert-butoxide (10.09 mg,0.90 mmol) was added and the reaction was heated to 120° C. After 8hours, the reaction was cooled, quenched with AcOH, diluted with MeOH,filtered through a syringe filter, and the crude material was purifiedvia preparative LC/MS with the following conditions: Column: XBridgeC18, 200 mm×19 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: a 0-minutehold at 0% B, 0-46% B over 25 minutes, then a 6-minute hold at 100% B;Flow Rate: 20 mL/min; Column Temperature: 25° C. Fraction collection wastriggered by MS signals. Fractions containing the desired product werecombined and dried via centrifugal evaporation. The material was furtherpurified via preparative LC/MS with the following conditions: Column:XBridge C18, 200 mm×19 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: a 0-minutehold at 0% B, 0-40% B over 20 minutes, then a 4-minute hold at 100% B;Flow Rate: 20 mL/min; Column Temperature: 25° C. Fraction collection wastriggered by MS and UV signals. Fractions containing the desired productwere combined and dried via centrifugal evaporation to give4-((2-amino-7-(1H-pyrazol-5-yl)quinolin-4-yl)oxy)butan-1-ol, TFA (5.2mg, 14%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.32-8.13 (m, 1H), 8.07-7.96 (m,2H), 7.93-7.81 (m, 2H), 6.84 (s, 1H), 6.36 (s, 1H), 4.29 (br t, J=6.3Hz, 2H), 3.55-3.34 (m, 2H), 1.98-1.86 (m, 2H), 1.73-1.60 (m, 2H). LC RT:1.04 min. M/Z=299.31.

Example II-6: Synthesis of a 4-amino Substituted Quinoline with anN-Linked Pyrazole

Step 1: Preparation of 4-chloro-7-(1H-pyrazol-1-yl)quinolin-2-amine

7-Bromo-4-chloroquinolin-2-amine (250 mg, 0.971 mmol), 1H-pyrazole (132mg, 1.942 mmol), copper(I) iodide (370 mg, 1.942 mmol), and sodiumcarbonate (412 mg, 3.88 mmol) were placed in a pressure vial. The vialwas placed under vacuum and backfilled with nitrogen three times. DMSO(9708 μl) was added and nitrogen was bubbled through the solution.N,N′-dimethylethane-1,2-diamine (257 mg, 2.91 mmol) was added and thereaction was heated to 120° C. After 4 hours, the reaction was cooled,diluted with water, and extracted three times with EtOAc. The organiclayers were washed with half water/half saturated ammonium hydroxidesolution, dried with sodium sulfate, and concentrated. The residue wasdissolved in DCM/MeOH and absorbed onto silica gel. The residue waspurified via ISCO (24 g column; DCM/MeOH; 0 to 10% gradient) to give4-chloro-7-(1H-pyrazol-1-yl)quinolin-2-amine (144 mg, 0.589 mmol, 60.6%yield). ¹H NMR (400 MHz, DMSO-d₆) δ 8.67 (d, J=2.5 Hz, 1H), 7.96 (d,J=8.9 Hz, 1H), 7.90 (d, J=2.0 Hz, 1H), 7.85-7.79 (m, 2H), 6.93 (s, 1H),6.77 (s, 2H), 6.61-6.57 (m, 1H).

Step 2: Preparation of3-((2-amino-7-(1H-pyrazol-1-yl)quinolin-4-yl)amino)propan-1-ol (Compound173)

To a solution of 4-chloro-7-(1H-pyrazol-1-yl)quinolin-2-amine (20 mg,0.082 mmol) and 3-aminopropan-1-ol (61.4 mg, 0.817 mmol) in DMSO (0.5mL) was added Hunig's base (0.043 mL, 0.245 mmol). The reaction washeated to 120° C. overnight. LC/MS showed that the reaction wascomplete. The reaction was cooled, diluted with MeOH and a small amountof AcOH, filtered through a syringe filter, and the crude material waspurified via preparative LC/MS with the following conditions: Column:XBridge C18, 200 mm×19 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: a 3-minutehold at 0% B, 0-38% B over 20 minutes, then a 4-minute hold at 100% B;Flow Rate: 20 mL/min; Column Temperature: 25° C. Fraction collection wastriggered by MS signals. Fractions containing the desired product werecombined and dried via centrifugal evaporation to give3-((2-amino-7-(1H-pyrazol-1-yl)quinolin-4-yl)amino)propan-1-ol (14.2 mg,61.3%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.55 (br s, 1H), 8.06 (br d, J=8.9Hz, 1H), 7.75 (br d, J=14.0 Hz, 2H), 7.61 (br d, J=7.9 Hz, 1H), 7.03 (brs, 1H), 6.68 (br s, 1H), 6.56 (br s, 1H), 5.72 (s, 1H), 3.52 (br s, 2H),3.30-3.17 (m, 2H), 1.84-1.77 (m, 2H). LC/MS conditions: Column: WatersXBridge C18, 2.1 mm×50 mm, 1.7 μm particles; Mobile Phase A: 5:95acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10 mM ammonium acetate; Temperature: 50° C.;Gradient: 0% B to 100% B over 3 min, then a 0.50 min hold at 100% B;Flow: 1 mL/min; Detection: MS and UV (220 nm). LC RT: 1.08 min.

M/Z=283.96.

Compound 174 to Compound 176, Compound 292 to Compound 309 were preparedaccording to the synthetic procedures described for Compound 173 fromthe appropriate starting materials.

Compd. LC/MS RT ¹H NMR No. Structure [M + H]⁺ (min) (500 MHz, DMSO-d₆)174

310.9 1.08 δ 8.55 (br s, 1H), 8.00 (br d, J = 8.9 Hz, 1H), 7.89 (br s,1H), 7.75 (br d, J = 17.4 Hz, 2H), 7.59 (br d, J = 7.9 Hz, 1H), 6.98 (brs, 1H), 6.55 (br s, 1H), 6.49 (br s, 1H), 5.74 (s, 1H), 3.55- 3.35 (m,2H), 2.59 (br d, J = 4.3 Hz, 3H). Two protons from sidechain are notvisible, likely due to overlap with suppressed water peak or lowintegration. 175

317.0 1.19 δ 8.60 (br s, 1H), 8.53 (br s, 1H), 8.45 (br d, J = 3.1 Hz,1H), 8.09 (br d, J = 8.9 Hz, 1H), 7.76 (br s, 2H), 7.71 (s, 1H), 7.67(br d, J = 4.6 Hz, 1H), 7.61 (br d, J = 9.2 Hz, 1H), 7.41-7.32 (m, 1H),6.56 (br s, 1H), 6.25-6.16 (m, 1H), 5.65 (s, 1H), 4.49 (br d, J = 5.2Hz, 2H) 176

297.9 1.11 δ 8.63 (br s, 1H), 8.37 (br d, J = 8.9 Hz, 1H), 7.97 (s, 1H),7.91-7.79 (m, 3H), 7.60 (br s, 2H), 6.64 (br s, 1H), 5.98 (s, 1H), 3.26(br d, J = 5.5 Hz, 2H), 1.24-1.16 (m, 6H) 292

306.1 0.82 δ 8.55 (s, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.76 (d, J = 1.5Hz, 1H), 7.72 (d, J = 2.3 Hz, 1H), 7.61-7.54 (m, 2H), 7.49-7.40 (m, 1H),6.61-6.52 (m, 1H), 6.35 (br d, J = 2.1 Hz, 1H), 6.21 (d, J = 2.1 Hz,1H), 5.78 (s, 1H), 4.42 (br d, J = 5.6 Hz, 2H) 293

331.2 1.2 δ 8.67-8.54 (m, 2H), 8.28- 8.16 (m, 2H), 8.03-7.94 (m, 2H),7.91-7.81 (m, 2H), 7.79- 7.66 (m, 1H), 7.56 (br d, J = 7.6 Hz, 1H),7.50-7.42 (m, 1H), 6.64 (d, J = 1.8 Hz, 1H), 5.88 (s, 1H), 3.68 (br s,2H), 3.23 (br t, J = 7.0 Hz, 2H) 294

307.0 0.78 δ 8.59 (d, J = 2.1 Hz, 1H), 8.30 (br s, 1H), 8.14 (d, J = 8.8Hz, 1H), 7.79 (s, 3H), 7.68 (dd, J = 8.9, 2.1 Hz, 1H), 6.67-6.48 (m,2H), 5.75 (s, 1H), 4.54 (br d, J = 5.8 Hz, 2H) 295

310.1 0.91 δ 8.57 (d, J = 2.1 Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.78(d, J = 1.2 Hz, 1H), 7.76 (d, J = 2.1 Hz, 1H), 7.63 (dd, J = 8.9, 2.1Hz, 1H), 6.58 (br d, J = 1.8 Hz, 2H), 6.41-6.35 (m, 1H), 5.82 (s, 1H),4.26 (br d, J = 2.4 Hz, 1H), 3.69-3.61 (m, 1H), 2.11- 1.98 (m, 1H),1.87-1.64 (m, 4H), 1.61-1.50 (m, 1H) 296

270.2 0.93^(a) δ 8.57 (d, J = 2.4 Hz, 1H), 8.11 (d, J = 9.2 Hz, 1H),7.78 (dd, J = 6.7, 1.5 Hz, 2H), 7.66 (dd, J = 8.9, 2.1 Hz, 1H), 7.14 (brs, 1H), 6.88 (br s, 1H), 6.58 (s, 1H), 5.77 (s, 1H), 3.78-3.61 (m, 1H),3.31 (q, J = 5.6 Hz, 2H). One of ethylene proton signals is minimizedlikely due to overlap with suppressed water. 297

337.1 1.14 δ 8.56 (d, J = 2.4 Hz, 1H), 8.04 (d, J = 8.9 Hz, 1H),7.84-7.72 (m, 2H), 7.64 (dd, J = 8.9, 2.1 Hz, 1H), 7.59 (d, J = 3.1 Hz,1H), 7.33-7.17 (m, 1H), 6.70 (br s, 1H), 6.57 (d, J = 1.5 Hz, 1H), 5.82(s, 1H), 3.71-3.54 (m, 1H), 3.40 (t, J = 7.0 Hz, 1H). ). Two of ethyleneproton signals are minimized likely due to overlap with suppressedwater. 298

306.1 0.74 δ 8.57 (d, J = 2.1 Hz, 1H), 8.13 (d, J = 8.8 Hz, 1H),7.85-7.76 (m, 2H), 7.68 (br dd, J = 8.9, 2.1 Hz, 2H), 6.96 (s, 2H), 6.77(br s, 1H), 6.58 (d, J = 1.5 Hz, 1H), 5.75 (s, 1H), 4.48 (br d, J = 5.5Hz, 2H) 299

367.2 1.26 ¹H NMR (500 MHz, DMSO-d₆) δ 8.76 (br d, J = 4.3 Hz, 1H), 8.58(d, J = 2.4 Hz, 1H), 8.13 (d, J = 9.2 Hz, 1H), 8.00 (td, J = 7.7, 1.7Hz, 1H), 7.80 (dd, J = 7.6, 1.8 Hz, 2H), 7.75 (d, J = 7.9 Hz, 1H), 7.69(dd, J = 8.9, 1.8 Hz, 1H), 7.64-7.52 (m, 2H), 6.71 (br s, 1H), 6.60-6.52(m, 1H), 5.97 (s, 1H), 4.18 (td, J = 14.7, 6.3 Hz, 2H) 300

317.2 0.96 δ 8.62-8.52 (m, 2H), 8.13 (d, J = 8.8 Hz, 1H), 7.81-7.72 (m,3H), 7.70-7.59 (m, 2H), 7.34 (d, J = 7.9 Hz, 1H), 7.32-7.26 (m, 1H),6.57 (d, J = 1.8 Hz, 1H), 6.16 (br s, 2H), 5.60 (s, 1H), 4.55 (d, J =5.8 Hz, 2H) 301

312.1 1.24 δ 8.57 (d, J = 2.1 Hz, 1H), 8.05 (d, J = 9.2 Hz, 1H), 7.79(s, 2H), 7.65 (dd, J = 8.9, 1.5 Hz, 1H), 7.22 (br d, J = 4.6 Hz, 1H),6.77 (br s, 1H), 6.58 (s, 1H), 5.73 (s, 1H), 3.34-3.22 (m, 2H), 1.84-1.73 (m, 2H), 1.20 (s, 6H) 302

320.2 1.04 δ 8.62-8.54 (m, 1H), 8.04 (d, J = 9.2 Hz, 1H), 7.81 (d, J =1.8 Hz, 1H), 7.79 (d, J = 1.2 Hz, 1H), 7.75 (d, J = 1.8 Hz, 1H), 7.69(dd, J = 9.0, 2.0 Hz, 1H), 7.49 (d, J = 1.2 Hz, 1H), 7.34 (br s, 1H),6.78-6.65 (m, 2H), 6.58 (d, J = 1.8 Hz, 1H), 6.26- 6.21 (m, 1H), 5.76(s, 1H), 4.43 (t, J = 6.4 Hz, 2H), 3.63 (q, J = 6.0 Hz, 2H) 303

337.1 1.01 δ 8.54 (d, J = 2.4 Hz, 1H), 8.13- 8.08 (m, 1H), 7.76 (d, J =1.2 Hz, 1H), 7.73 (d, J = 2.1 Hz, 1H), 7.61 (br dd, J = 8.9, 2.1 Hz,2H), 7.21 (s, 1H), 6.62-6.48 (m, 2H), 6.41-6.37 (m, 1H), 5.72 (s, 1H),4.48 (br d, J = 5.8 Hz, 2H), 2.63 (s, 3H) 304

310.1 0.93 δ 8.62-8.52 (m, 1H), 8.06 (d, J = 9.2 Hz, 1H), 7.77 (s, 1H),7.74 (d, J = 1.8 Hz, 1H), 7.62 (dd, J = 8.7, 2.0 Hz, 1H), 6.63- 6.58 (m,1H), 6.56 (d, J = 1.8 Hz, 1H), 6.44-6.35 (m, 1H), 5.81 (s, 1H), 4.24 (brd, J = 2.4 Hz, 1H), 2.07-1.98 (m, 1H), 1.85-1.80 (m, 1H), 1.79-1.71 (m,2H), 1.70-1.62 (m, 1H), 1.60-1.50 (m, 2H). Several protons fromcyclopentyl ring are not visible, likely due to overlap with water/DMSO.305

332.1 0.99 δ 8.62-8.56 (m, 1H), 8.04 (d, J = 8.8 Hz, 1H), 7.80 (d, J =2.1 Hz, 1H), 7.79 (d, J = 1.2 Hz, 1H), 7.68 (dd, J = 9.0, 1.7 Hz, 1H),7.34-7.24 (m, 1H), 6.65- 6.53 (m, 3H), 5.80 (s, 1H), 3.74- 3.62 (m, 2H),3.58-3.47 (m, 1H), 3.08 (s, 3H). A proton from ethyl chain is notvisible, likely due to overlap with water/DMSO. 306

311.1 0.77 δ 8.60-8.52 (m, 1H), 8.14 (br t, J = 5.2 Hz, 1H), 7.99 (d, J= 8.5 Hz, 1H), 7.77 (d, J = 1.2 Hz, 1H), 7.75 (d, J = 2.1 Hz, 1H), 7.62(dd, J = 9.0, 2.0 Hz, 1H), 7.05 (br s, 1H), 6.60-6.51 (m, 2H), 5.73 (s,1H), 1.85 (s, 3H). Several protons from ethyl chain is not visible,likely due to overlap with water/DMSO. 307

306.1 0.97 δ 8.94-8.90 (m, 1H), 8.65 (d, J = 2.4 Hz, 1H), 8.62-8.57 (m,1H), 8.30 (br d, J = 9.2 Hz, 1H), 8.01 (d, J = 1.8 Hz, 1H), 7.97- 7.91(m, 1H), 7.90-7.81 (m, 3H), 7.61-7.57 (m, 1H), 6.67- 6.60 (m, 1H), 5.82(s, 1H), 4.63 (br d, J = 5.2 Hz, 2H) 308

321.1 0.74 δ 8.57 (d, J = 2.1 Hz, 1H), 8.50 (s, 1H), 8.01 (d, J = 10.0Hz, 2H), 7.79 (dd, J = 3.5, 1.7 Hz, 2H), 7.66 (dd, J = 8.9, 1.8 Hz, 1H),7.27 (br s, 1H), 6.64-6.56 (m, 2H), 5.76 (s, 1H), 4.49 (t, J = 6.0 Hz,2H), 3.76-3.55 (m, 2H) 309

318.1 1.11 δ 9.17-9.10 (m, 1H), 8.54 (br d, J = 2.5 Hz, 1H), 8.12 (d, J= 9.2 Hz, 1H), 8.00-7.89 (m, 1H), 7.77 (d, J = 1.2 Hz, 1H), 7.74 (d, J =1.9 Hz, 1H), 7.69-7.66 (m, 1H), 7.65 (d, J = 4.7 Hz, 1H), 7.64-7.61 (m,1H), 6.59-6.54 (m, 1H), 6.48-6.34 (m, 1H), 5.64 (s, 1H), 4.77 (br d, J =5.6 Hz, 2H) ^(a)LC/MS conditions: Column: Waters XBridge C18, 2.1 mm ×50 mm, 1.7 μm particles; Mobile Phase A: 5:95 acetonitrile:water with0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with0.1% trifluoroacetic acid; Temperature: 50° C.; Gradient: 0% B to 100% Bover 3 min, then a 0.50 min hold at 100% B; Flow: 1 mL/min; Detection:MS and UV (220 nm).

Example II-7: Synthesis of a 4-Ether Substituted Quinoline with anN-Linked Pyrazole

Step 1: Preparation ofN-(2-((2-amino-7-(1H-pyrazol-1-yl)quinolin-4-yl)oxy)ethyl)acetamide, TFA(Compound 177)

To a solution of N-(2-hydroxyethyl)acetamide (63.2 mg, 0.613 mmol) and4-chloro-7-(1H-pyrazol-1-yl)quinolin-2-amine (20 mg, 0.082 mmol) in NMP(0.5 mL) was added potassium tert-butoxide (22.93 mg, 0.204 mmol). Thereaction was heated to 100° C. overnight. Then, the temperature wasincreased to 120° C., and the reaction was heated overnight. Potassiumtert-butoxide (11.5 mg, 0.102 mmol) was added, and the reaction washeated for a further 6 hours. The reaction was cooled, diluted with MeOHand a small amount of AcOH, and the crude material was purified viapreparative LC/MS with the following conditions: Column: XBridge C18,200 mm×19 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:waterwith 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:waterwith 10-mM ammonium acetate; Gradient: a 0-minute hold at 1% B, 1-41% Bover 20 minutes, then a 4-minute hold at 100% B; Flow Rate: 20 mL/min;Column Temperature: 25° C. Fraction collection was triggered by MSsignals. Fractions containing the desired product were combined anddried via centrifugal evaporation. The material was further purified viapreparative LC/MS with the following conditions: Column: XBridge C18,200 mm×19 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:waterwith 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:waterwith 0.1% trifluoroacetic acid; Gradient: a 4-minute hold at 0% B, 0-32%B over 25 minutes, then a 6-minute hold at 100% B; Flow Rate: 20 mL/min;Column Temperature: 25° C. Fraction collection was triggered by MSsignals. Fractions containing the desired product were combined anddried via centrifugal evaporation to giveN-(2-((2-amino-7-(1H-pyrazol-1-yl)quinolin-4-yl)oxy)ethyl)acetamide, TFA(2.8 mg, 8.1%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.59 (br s, 1H), 8.23 (br s,1H), 8.01 (br d, J=8.8 Hz, 1H), 7.79 (br d, J=8.9 Hz, 2H), 7.67 (br d,J=8.5 Hz, 1H), 6.57 (br s, 1H), 6.18 (s, 1H), 4.12 (br t, J=4.7 Hz, 2H),3.56 (br d, J=5.5 Hz, 1H), 1.86 (s, 3H). One proton from sidechain isnot visible due to low integration or overlap with suppressed waterpeak. LC/MS Conditions: Column: Waters Acquity UPLC BEH C18, 2.1×50 mm,1.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mMammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mMammonium acetate; Temperature: 50° C.; Gradient: 0-100% B over 3minutes, then a 0.75-minute hold at 100% B; Flow: 1.0 mL/min; Detection:UV at 220 nm. LC RT: 1.09 min. M/Z=312.1.

Example II-8: Preparation of a 4-ether Substituted Quinoline with aC-Linked Pyrazole

Step 1: Preparation of2-((2-amino-7-(1H-pyrazol-5-yl)quinolin-4-yl)oxy)ethan-1-ol (Compound178)

To a solution of4-chloro-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)quinolin-2-amine(80 mg, 0.243 mmol) and ethane-1,2-diol (151 mg, 2.433 mmol) in NMP(1622 μl) was added potassium tert-butoxide (54.6 mg, 0.487 mmol). Thereaction was heated to 100° C. overnight. LC/MS showed the reaction wascomplete. The reaction was cooled, diluted with water, and extractedthree times with EtOAc. The organic layers were concentrated. Theresidue was dissolved in 1 mL DCM and 1 mL TFA. After 2 hours, LC/MSshowed that the reaction was complete and that some trifluoroacetateester had formed. The reaction was concentrated and azeotroped with DCM.The residue was dissolved in 1 mL MeOH and potassium carbonate (67.3 mg,0.487 mmol) was added. After 1.5 hours, LC/MS showed that thetrifluoroacetate ester had been completely hydrolyzed. The reaction wasconcentrated. The residue was purified via ISCO (24 g column; DCM/MeOH;0 to 20% gradient) to give2-((2-amino-7-(1H-pyrazol-5-yl)quinolin-4-yl)oxy)ethan-1-ol (28 mg,41.3% yield). ¹H NMR (400 MHz, METHANOL-d₄) δ 8.23 (d, J=8.5 Hz, 1H),8.00-7.88 (m, 2H), 7.78 (br s, 1H), 6.85 (d, J=2.2 Hz, 1H), 6.37 (s,1H), 4.37 (t, J=4.5 Hz, 2H), 4.09-4.01 (m, 2H). LC/MS conditions:Column: Waters XBridge C18, 2.1 mm×50 mm, 1.7 μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50°C.; Gradient: 0% B to 100% B over 3 min, then a 0.75 min hold at 100% B;Flow: 1 mL/min; Detection: MS and UV (220 nm). LC RT: 0.71 min.M/Z=271.24.

Compound 179 to Compound 201, Compound 310 to Compound 312 were preparedaccording to the synthetic procedures described for Compound 178 fromthe appropriate starting materials.

Compd. LC/MS RT ¹H NMR No. Structure [M + H]⁺ (min) (500 MHz, DMSO-d₆)179

285.4 0.93 δ 8.05-7.96 (m, 2H), 7.89 (br d, J = 8.8 Hz, 1H), 7.81 (br s,1H), 6.83 (d, J = 2.2 Hz, 1H), 6.39 (s, 1H), 4.35 (t, J = 6.2 Hz, 2H),3.66 (br t, J = 6.1 Hz, 2H), 2.05 (quin, J = 6.2 Hz, 2H) 180

416.2 1.25 δ 7.87 (d, J = 8.4 Hz, 1H), 7.83 (s, 1H), 7.71 (br s, 1H),7.64 (br s, 1H), 6.75 (s, 1H), 6.23 (s, 1H), 4.17 (t, J = 6.3 Hz, 2H),3.04 (br d, J = 4.9 Hz, 4H), 2.96- 2.87 (m, 4H), 2.57 (br t, J = 7.2 Hz,2H), 1.88 (quin, J = 6.8 Hz, 2H), 1.66 (quin, J = 7.2 Hz, 2H) 181

352.1 1.11 δ 7.94 (br d, J = 8.5 Hz, 1H), 7.90 (br s, 1H), 7.83-7.68 (m,2H), 6.81 (s, 1H), 6.23 (s, 1H), 4.17 (br t, J = 5.6 Hz, 2H), 2.24- 2.15(m, 2H), 2.12-2.02 (m, 2H), 1.95-1.84 (m, 2H) Two methylenes are notvisible in NMR; probably due to overlap with suppressed water peak. 182

269.0 1.59 δ 8.40-8.19 (m, 1H), 8.06- 7.97 (m, 2H), 7.93-7.83 (m, 2H),6.84 (s, 1H), 6.37 (s, 1H), 4.23 (br t, J = 6.3 Hz, 2H), 1.96- 1.84 (m,2H), 1.07 (t, J = 7.3 Hz, 3H) 183

338.1 1.13 δ 8.11-8.01 (m, 2H), 7.93 (br d, J = 8.4 Hz, 1H), 7.83 (br s,1H), 6.83 (d, J = 2.2 Hz, 1H), 6.33 (s, 1H), 5.14 (s, 2H), 3.51 (br t, J= 6.7 Hz, 2H), 3.38 (br t, J = 6.9 Hz, 2H), 2.00-1.90 (m, 2H), 1.86-1.75(m, 2H) 184

381.0 1.21 δ 7.84 (d, J = 8.4 Hz, 1H), 7.78 (s, 1H), 7.69 (s, 1H), 7.56(br d, J = 7.8 Hz, 1H), 6.73 (d, J = 1.9 Hz, 1H), 6.19 (s, 1H), 4.13 (t,J = 6.4 Hz, 2H), 2.42-2.26 (m, 8H), 2.13 (s, 2H), 1.87-1.81 (m, 2H),1.69-1.59 (m 2H) One methylene from sidechain is not visible in NMR,likely due to overlap with suppressed water peak. 185

299.1 1.30 δ 7.85 (d, J = 8.4 Hz, 1H), 7.80 (s, 1H), 7.70 (s, 1H), 7.58(br d, J = 8.6 Hz, 1H), 6.74 (d, J = 1.9 Hz, 1H), 6.22 (s, 1H), 4.29-4.19 (m, 2H), 3.88-3.79 (m, 2H), 3.58 (q, J = 7.0 Hz, 2H), 1.15 (t, J =7.0 Hz, 3H) 186

311.3 1.05 δ 8.10-7.98 (m, 2H), 7.92 (br d, J = 8.2 Hz, 1H), 7.86 (br s,1H), 6.85 (s, 1H), 6.47 (s, 1H), 4.98-4.86 (m, 1H), 3.97-3.88 (m, 2H),3.59 (br t, J = 8.5 Hz, 1H), 3.42-3.31 (m, 1H), 2.11 (br d, J = 9.8 Hz,2H), 1.82 (br d, J = 8.5 Hz, 2H) 187

325.2 1.30 δ 8.02 (br d, J = 8.4 Hz, 2H), 7.92-7.77 (m, 2H), 6.82 (d, J= 1.9 Hz, 1H), 6.40 (s, 1H), 4.15 (d, J = 6.2 Hz, 2H), 3.93 (br dd, J =11.2, 3.0 Hz, 2H), 3.41 (br t, J = 10.9 Hz, 1H), 2.21 (br s, 1H), 1.77(br d, J = 11.1 Hz, 2H), 1.47 (qd, J = 12.2, 4.4 Hz, 2H). One proton ismissing from THP sidechain, likely due to overlap with suppressed waterpeak. 188

312.3 0.97 δ 8.10 (br s, 1H), 8.04 (d, J = 8.5 Hz, 1H), 7.93 (br s, 1H),7.78 (br s, 2H), 6.83-6.77 (m, 1H), 6.30 (s, 1H), 4.22 (br t, J = 5.0Hz, 2H), 3.59 (q, J = 5.3 Hz, 2H), 1.86 (s, 3H) 189

318.0 1.12 δ 8.62 (br d, J = 4.3 Hz, 1H), 7.95 (br d, J = 8.2 Hz, 1H),7.92- 7.86 (m, 1H), 7.81 (s, 1H), 7.73 (br s, 1H), 7.65-7.56 (m, 2H),7.42-7.36 (m, 1H), 6.78 (s, 1H), 6.31 (br s, 2H), 6.26 (s, 1H), 5.33 (s,2H) 190

318.1 1.06 δ 8.77 (s, 1H), 8.60 (br d, J = 4.3 Hz, 1H), 7.98 (br d, J =7.6 Hz, 1H), 7.85 (br d, J = 8.5 Hz, 1H), 7.80 (s, 1H), 7.72 (br s, 1H),7.57 (br d, J = 8.2 Hz, 1H), 7.51- 7.45 (m, 1H), 6.77 (s, 1H), 6.32 (brd, J = 7.9 Hz, 3H), 5.31 (s, 2H) 191

325.3 0.99 δ 7.84-7.75 (m, 2H), 7.71 (br s, 1H), 7.55 (br d, J = 8.2 Hz,1H), 6.75 (s, 1H), 6.22 (br d, J = 9.2 Hz, 2H), 4.45 (br d, J = 3.7 Hz,1H), 3.62 (br s, 1H), 2.17-2.05 (m, 2H), 1.89 (br s, 2H), 1.65-1.53 (m,2H), 1.45- 1.30 (m, 2H) 192

311.0 1.02 δ 8.33-8.12 (m, 1H), 8.03 (br d, J = 7.9 Hz, 2H), 7.96-7.80(m, 2H), 6.85 (s, 1H), 6.34 (s, 1H), 4.18 (s, 2H), 0.63 (br d, J = 11.0Hz, 4H). One Methylene from sidechain is missing, likely due to overlapwith suppressed water peak. 193

299.4 1.10 δ 8.02 (br d, J = 8.2 Hz, 2H), 7.98-7.80 (m, 2H), 6.85 (s,1H), 6.37 (s, 1H), 4.32 (br t, J = 6.0 Hz, 2H), 3.61-3.40 (m, 2H)(overlaps suppressed water peak), 3.27 (s, 2H), 2.19-2.06 (m, 2H) 194

329.3 0.82 δ 8.00 (br d, J = 8.2 Hz, 2H), 7.88 (br d, J = 9.8 Hz, 2H),6.84 (br s, 1H), 6.38 (s, 1H), 4.06 (br s, 2H), 3.24 (br s, 2H), 1.00(s, 3H). One methylene from sidechain is missing in NMR, likely due tooverlap with suppressed water peak. 195

313.2 1.22 δ 7.86-7.77 (m, 2H), 7.72 (br s, 1H), 7.57 (br d, J = 7.6 Hz,1H), 6.77 (s, 1H), 6.30 (br s, 2H), 6.21 (s, 1H), 4.23 (br t, J = 6.7Hz, 2H), 1.99 (br t, J = 6.7 Hz, 2H), 1.22 (s, 6H) 196

335.3 1.07 δ 7.87 (br d, J = 8.5 Hz, 1H), 7.81-7.68 (m, 3H), 7.58 (br d,J = 7.0 Hz, 1H), 7.46 (s, 1H), 6.77 (s, 1H), 6.25 (br d, J = 11.0 Hz,3H), 6.11 (s, 1H), 4.38 (br t, J = 6.6 Hz, 2H), 4.05 (br t, J = 5.6 Hz,2H), 2.36 (br t, J = 6.1 Hz, 2H) 197

313.2 0.79 δ 8.09 (br d, J = 8.5 Hz, 1H), 7.99-7.69 (m, 3H), 6.82 (br s,1H), 6.34 (br s, 1H), 4.97 (br s, 1H), 4.58-4.44 (m, 1H), 4.16 (br dd, J= 9.5, 5.5 Hz, 1H), 4.03-3.86 (m, 2H), 3.79-3.64 (m, 2H) 198

339.2 0.82 δ 7.84 (br d, J = 8.2 Hz, 1H), 7.78 (s, 1H), 7.75-7.50 (m,2H), 6.76 (s, 1H), 6.35 (s, 1H), 6.24 (br s, 2H), 6.18 (s, 1H), 4.18 (brs, 2H), 3.60-3.38 (m, 4H) (overlaps suppressed water peak), 3.24 (br t,J = 7.8 Hz, 2H) 199

310.0 1.06 δ 8.19 (br s, 1H), 7.84-7.77 (m, 2H), 7.72 (br d, J = 4.9 Hz,1H), 7.57 (br d, J = 7.6 Hz, 1H), 6.77 (s, 1H), 6.34 (s, 1H), 6.28 (brs, 2H), 5.02 (br t, J = 7.5 Hz, 1H), 2.74-2.62 (m, 1H), 2.19- 2.06 (m,1H). Two protons are not visible, possibly due to overlap withsuppressed water peak or low integration. 200

326.0 0.79 δ 8.02-7.65 (m, 5H), 6.80 (br s, 1H), 6.24 (s, 1H), 4.18 (brs, 2H), 2.00 (br t, J = 6.3 Hz, 2H), 1.81 (s, 3H). Two protons fromsidechain are not visible, likely due to overlap with suppressed waterpeak. 201

321.3 1.13 δ 8.08 (s, 1H), 8.01-7.90 (m, 2H), 7.84-7.62 (m, 3H), 6.81(br d, J = 15.9 Hz, 2H), 6.67 (br s, 1H), 3.71-3.55 (m, 2H), 2.69 (br t,J = 6.7 Hz, 2H) 310

313.3 1.05 δ 7.89 (d, J = 8.5 Hz, 1H), 7.83 (s, 1H), 7.75 (br s, 1H),7.70- 7.54 (m, 1H), 6.79 (d, J = 1.8 Hz, 2H), 6.53 (br s, 2H), 6.22 (s,1H), 3.87 (s, 2H), 3.39 (br s, 1H), 1.03 (s, 6H). One methylene is notvisible, possibly due to overlap with suppressed water peak. 311

322.0 1.01 δ 8.02-7.91 (m, 3H), 7.87- 7.72 (m, 2H), 6.82 (s, 1H), 6.46(s, 1H), 5.57 (br s, 2H), 4.11 (s, 3H) 312

322.2 1.00 δ 8.05-7.98 (m, 3H), 7.92- 7.83 (m, 2H), 6.85 (d, J = 2.1 Hz,1H), 6.54 (s, 1H), 5.65 (s, 2H), 3.97 (s, 3H)

Example II-9: Synthesis of2-((2-amino-7-(1H-pyrazol-5-yl)quinolin-4-yl)oxy)propane-1,3-diol

Step 1: Preparation of2-((2-amino-7-(1H-pyrazol-5-yl)quinolin-4-yl)oxy)propane-1,3-diol(Compound 202)

To a solution of 2-phenyl-1,3-dioxan-5-ol (110 mg, 0.608 mmol) and4-chloro-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)quinolin-2-amine(20 mg, 0.061 mmol) in NMP (406 μl) was added potassium tert-butoxide(17.06 mg, 0.152 mmol). The reaction was heated to 100° C. After 5hours, the reaction was cooled, diluted with water, and extracted threetimes with EtOAC. The organic layers were concentrated. The residue wasdissolved in 0.8 mL MeOH, and 0.2 mL concentrated HCl was added. After 4hours, 0.2 mL HCl was added. After a further 4 hours, the reaction washeated to 50° C. overnight. The reaction was concentrated and azeotropedwith MeOH. The residue was dissolved in MeOH, neutralized with solidK₂CO₃, filtered through a syringe filter, and the crude material waspurified via preparative LC/MS with the following conditions: Column:XBridge C18, 200 mm×19 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: a 0-minutehold at 0% B, 0-40% B over minutes, then a 4-minute hold at 100% B; FlowRate: 20 mL/min; Column Temperature: 25° C. Fraction collection wastriggered by UV signals. Fractions containing the desired product werecombined and dried via centrifugal evaporation to give2-((2-amino-7-(1H-pyrazol-5-yl)quinolin-4-yl)oxy)propane-1,3-diol (4.1mg, 28.1%). ¹H NMR (500 MHz, DMSO-d₆) δ 7.94 (br d, J=8.2 Hz, 1H), 7.81(s, 1H), 7.74 (br s, 1H), 7.60 (br d, J=7.6 Hz, 1H), 6.78 (s, 1H), 6.52(br s, 1H), 6.30 (s, 1H), 4.49-4.40 (m, 1H), 3.81-3.61 (m, 4H). LC/MSConditions: Column: Waters XBridge C18, 2.1 mm×50 mm, 1.7 μm particles;Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate;Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate;Temperature: 50° C.; Gradient: 0% B to 100% B over 3 min, then a 0.50min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). LCRT: 0.56 min.

M/Z=301.0.

Example II-10: Synthesis of 4-diaminoethane Substituted Quinolines

Step 1: Preparation of tert-butyl(2-((2-amino-7-bromoquinolin-4-yl)amino)ethyl)carbamate

To a solution of 7-bromo-4-chloroquinolin-2-amine (200 mg, 0.777 mmol)and tert-butyl (2-aminoethyl)carbamate (622 mg, 3.88 mmol) in DMSO (3883μl) was added Hunig's Base (407 μl, 2.330 mmol). The reaction was heatedto 120° C. overnight. The reaction was diluted with water and extractedthree times with EtOAc. The organic layers were dried with sodiumsulfate and concentrated. The residue was purified via ISCO (24 gcolumn; DCM/MeOH;0 to 20% gradient). The material was triturated withDCM/hexanes to give tert-butyl(2-((2-amino-7-bromoquinolin-4-yl)amino)ethyl)carbamate (170 mg, 57.4%yield) containing a small amount of residual tert-butyl(2-aminoethyl)carbamate. This material was used in the next step withoutfurther purification. ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.79 (d, J=2.0Hz, 1H), 7.54 (d, J=8.7 Hz, 1H), 7.32-7.28 (m, 1H), 6.71 (br d, J=1.2Hz, 1H), 6.12-5.87 (m, 2H), 5.53 (s, 1H), 5.14-5.04 (m, 1H), 3.63-3.53(m, 2H), 3.36-3.26 (m, 2H), 1.48 (s, 9H).

Step 2: Preparation of tert-butyl(2-((2-amino-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)quinolin-4-yl)amino)ethyl)carbamate

1-(Tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(171 mg, 0.613 mmol), tert-butyl(2-((2-amino-7-bromoquinolin-4-yl)amino)ethyl)carbamate (187 mg, 0.490mmol), and PdCl₂(dppf)-DCM adduct (40.1 mg, 0.049 mmol) were placed in apressure vial. The vial was placed under vacuum and backfilled withnitrogen three times. Dioxane (3270 μl) and tripotassium phosphate (2Maqueous) (736 μl, 1.471 mmol) were added and nitrogen was bubbledthrough the solution. The vial was capped and heated to 100° C.overnight. The reaction was cooled, diluted with water, and extractedthree times with EtOAc. The organic layers were washed with brine, driedwith sodium sulfate and concentrated. The residue was purified via ISCO(12 g column; DCM/MeOH;0 to 20% gradient) to give tert-butyl(2-((2-amino-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)quinolin-4-yl)amino)ethyl)carbamate(160 mg, 0.354 mmol, 72.1% yield). ¹H NMR (400 MHz, CHLOROFORM-d) δ 7.77(d, J=8.5 Hz, 1H), 7.72 (s, 1H), 7.60 (d, J=1.5 Hz, 1H), 7.34 (br d,J=8.4 Hz, 1H), 6.85 (br s, 1H), 6.68-6.43 (m, 1H), 6.40 (d, J=1.7 Hz,1H), 5.63 (s, 1H), 5.57 (br t, J=5.8 Hz, 1H), 5.25 (dd, J=10.2, 1.9 Hz,1H), 4.13 (br dd, J=9.4, 1.6 Hz, 1H), 3.66-3.57 (m, 1H), 3.52 (br d,J=4.4 Hz, 2H), 3.28 (br d, J=3.3 Hz, 2H), 2.63-2.47 (m, 1H), 2.01 (br s,1H), 1.86 (br d, J=12.7 Hz, 1H), 1.80-1.66 (m, 1H), 1.62-1.49 (m, 2H),1.48-1.44 (m, 9H).

Step 3: Preparation ofN4-(2-aminoethyl)-7-(1H-pyrazol-5-yl)quinoline-2,4-diamine

4M HCl in dioxane (3535 μl) was added to tert-butyl(2-((2-amino-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)quinolin-4-yl)amino)ethyl)carbamate(160 mg, 0.354 mmol). After 2 hours, the reaction was concentrated andazeotroped twice with DCM. 217 mg material was obtained and taken on tonext reaction, assuming 50% purity. ¹H NMR (500 MHz, DMSO-d₆) δ 8.20 (brd, J=8.5 Hz, 1H), 8.06-7.95 (m, 2H), 7.87 (br d, J=8.5 Hz, 4H), 6.86 (brs, 1H), 5.87 (s, 1H), 3.55 (br d, J=4.6 Hz, 2H), 3.21 (br d, J=5.2 Hz,1H). One proton from sidechain is not visible, likely due to overlapwith suppressed water peak.

Step 4: Preparation ofN-(2-((2-amino-7-(1H-pyrazol-5-yl)quinolin-4-yl)amino)ethyl)-2-methylthiazole-4-carboxamide,TFA (Compound 203)

N4-(2-Aminoethyl)-7-(1H-pyrazol-5-yl)quinoline-2,4-diamine (30 mg, 0.056mmol) (assumed to be 50% by weight HCl) and2-methylthiazole-4-carboxylic acid (16.01 mg, 0.112 mmol) were dissolvedin DMF (0.4 mL). Triethylamine (0.078 mL, 0.559 mmol) and T3P (50% inDMF) (49.8 mg, 0.078 mmol) were added. After 2 hours, the reaction wasquenched with MeOH, filtered through a syringe filter, and the crudematerial was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 200 mm×19 mm, 5-μm particles; MobilePhase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; MobilePhase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid;Gradient: a 0-minute hold at 0% B, 0-40% B over 20 minutes, then a4-minute hold at 100% B; Flow Rate: 20 mL/min; Column Temperature: 25°C. Fraction collection was triggered by MS and UV signals. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to giveN-(2-((2-amino-7-(1H-pyrazol-5-yl)quinolin-4-yl)amino)ethyl)-2-methylthiazole-4-carboxamide,TFA (15.1 mg, 52.5%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.69 (br s, 1H), 8.16(br d, J=8.5 Hz, 1H), 8.11-8.04 (m, 2H), 7.92 (br s, 1H), 7.87-7.77 (m,2H), 7.59 (br s, 2H), 6.85 (s, 1H), 5.85 (s, 1H), 3.67-3.35 (m, 4H),2.68 (s, 3H). LC RT: 1.07 min. M/Z=394.34.

Compound 204 was prepared according to the synthetic proceduresdescribed for Compound 203 from the appropriate starting material

¹H NMR (500 MHz, DMSO-d₆) δ 9.22-9.06 (m, 1H), 8.65 (br d, J=4.3 Hz,1H), 8.11-8.04 (m, 1H), 8.03-7.93 (m, 2H), 7.77 (s, 1H), 7.72 (br s,1H), 7.63-7.51 (m, 2H), 7.03 (br s, 1H), 6.77 (s, 1H), 6.51 (br s, 1H),5.78 (s, 1H), 3.67 (br d, J=6.1 Hz, 1H), 3.51-3.33 (m, 1H). Two protonsfrom sidechain are not visible, likely due to low integration or overlapwith suppressed water peak. LC RT: 1.06 min. M/Z=374.3.

Example II-11: Preparation of methyl(2-((2-amino-7-(1H-pyrazol-5-yl)quinolin-4-yl)amino)ethyl)carbamate(Compound 205)

To a suspension ofN4-(2-aminoethyl)-7-(1H-pyrazol-5-yl)quinoline-2,4-diamine (30 mg, 0.056mmol) (assumed to be 50% HCl by weight) in DMF (0.4 mL) was added methylchloroformate (6.49 μl, 0.084 mmol). After 1.5 hours, 4 μL methylchloroformate was added. After 40 minutes, the reaction was quenchedwith MeOH. K₂CO₃ was added, and the reaction was stirred overnight. Thereaction was quenched with AcOH, filtered through a syringe filter, andthe crude material was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 200 mm×19 mm, 5-μm particles; MobilePhase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; MobilePhase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid;Gradient: a 0-minute hold at 0% B, 0-40% B over 20 minutes, then a4-minute hold at 100% B; Flow Rate: 20 mL/min; Column Temperature: 25°C. Fraction collection was triggered by MS signals. Fractions containingthe desired product were combined and dried via centrifugal evaporation.

The material was further purified via preparative LC/MS with thefollowing conditions: Column: XBridge C18, 200 mm×19 mm, 5-μm particles;Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate;Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate;Gradient: a 0-minute hold at 0% B, 0-60% B over 40 minutes, then a4-minute hold at 100% B; Flow Rate: 20 mL/min; Column Temperature: 25°C. Fraction collection was triggered by UV signals. Fractions containingthe desired product were combined and dried via centrifugal evaporationto give methyl(2-((2-amino-7-(1H-pyrazol-5-yl)quinolin-4-yl)amino)ethyl)carbamate (3.6mg, 19.3%). ¹H NMR (500 MHz, DMSO-d₆) δ 7.96 (br d, J=7.9 Hz, 1H),7.86-7.71 (m, 2H), 7.64 (br d, J=6.7 Hz, 1H), 7.33-7.17 (m, 1H), 6.83(br s, 1H), 5.83-5.69 (m, 1H), 3.55-3.46 (m, 2H), 3.37-3.22 (m, 3H). Twoprotons from sidechain are not visible, likely due to overlap withsuppressed water peak. LC/MS Conditions: Column: Waters XBridge C18, 2.1mm×50 mm, 1.7 μm particles; Mobile Phase A: 5:95 acetonitrile:water with10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10mM ammonium acetate; Temperature: 50° C.; Gradient: 0% B to 100% B over3 min, then a 0.50 min hold at 100% B; Flow: 1 mL/min; Detection: MS andUV (220 nm). LC RT: 0.89 min. M/Z=327.12.

Example II-12: Preparation ofN-(2-((2-amino-7-(1H-pyrazol-5-yl)quinolin-4-yl)amino)ethyl)methanesulfonamide,TFA (Compound 206)

To a suspension ofN4-(2-aminoethyl)-7-(1H-pyrazol-5-yl)quinoline-2,4-diamine (30 mg, 0.056mmol) (assumed to be 50% HCl by weight) in DMF (0.4 mL) was added MsCl(6.53 μl, 0.084 mmol). After 1.5 hours, 3.5 μL MsCl was added. After 40minutes, the reaction was quenched with MeOH, filtered through a syringefilter, and the crude material was purified via preparative LC/MS withthe following conditions: Column: XBridge C18, 200 mm×19 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 0.1%trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1%trifluoroacetic acid; Gradient: a 0-minute hold at 0% B, 0-40% B over 20minutes, then a 4-minute hold at 100% B; Flow Rate: 20 mL/min; ColumnTemperature: 25° C. Fraction collection was triggered by MS signals.Fractions containing the desired product were combined and dried viacentrifugal evaporation to giveN-(2-((2-amino-7-(1H-pyrazol-5-yl)quinolin-4-yl)amino)ethyl)methanesulfonamide,TFA (5.7 mg, 21.5%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.17 (br d, J=8.5 Hz,1H), 8.04 (br s, 1H), 7.93 (br s, 1H), 7.85 (br d, J=9.2 Hz, 2H), 7.62(br s, 2H), 7.29 (br t, J=5.8 Hz, 1H), 6.86 (s, 1H), 3.43 (br d, J=5.5Hz, 2H), 3.28 (br d, J=5.8 Hz, 2H), 2.93 (s, 3H). Column: Waters XBridgeC18, 2.1 mm×50 mm, 1.7 μm particles; Mobile Phase A: 5:95acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10 mM ammonium acetate; Temperature: 50° C.;Gradient: 0% B to 100% B over 3 min, then a 0.50 min hold at 100% B;Flow: 1 mL/min; Detection: MS and UV (220 nm). LC RT: 0.85 min.M/Z=347.27.

Example II-13: Preparation of1-(2-((2-amino-7-(1H-pyrazol-5-yl)quinolin-4-yl)amino)ethyl)-3-ethylurea,TFA (Compound 207)

To a suspension ofN4-(2-aminoethyl)-7-(1H-pyrazol-5-yl)quinoline-2,4-diamine (30 mg, 0.056mmol) (assumed to be 50% HCl by weight) in DMF (0.4 mL) was added ethylisocyanate (6.64 μl, 0.084 mmol). After 40 minutes, the reaction wasquenched with MeOH, filtered through a syringe filter, and the crudematerial was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 200 mm×19 mm, 5-μm particles; MobilePhase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; MobilePhase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid;Gradient: a 0-minute hold at 0% B, 0-40% B over 20 minutes, then a4-minute hold at 100% B; Flow Rate: 20 mL/min; Column Temperature: 25°C. Fraction collection was triggered by MS signals. Fractions containingthe desired product were combined and dried via centrifugal evaporationto give1-(2-((2-amino-7-(1H-pyrazol-5-yl)quinolin-4-yl)amino)ethyl)-3-ethylurea(7.3, 38.5%). ¹H NMR (500 MHz, DMSO-d₆) δ 12.36 (br s, 1H), 8.43-8.31(m, 1H), 8.12 (br d, J=8.5 Hz, 1H), 7.94 (s, 1H), 7.88-7.78 (m, 2H),7.63 (br s, 2H), 6.86 (s, 1H), 5.79 (s, 1H), 3.44-3.25 (m, 2H), 3.04 (brd, J=6.7 Hz, 2H), 0.99 (t, J=7.2 Hz, 3H). One methylene from sidechainis missing, likely due to overlap with suppressed water peak. LC RT:1.07 min. M/Z=339.94.

Example II-14: Preparation of3-(2-((2-amino-7-(1H-pyrazol-5-yl)quinolin-4-yl)amino)ethyl)-1,1-dimethylurea(Compound 208)

To a suspension ofN4-(2-aminoethyl)-7-(1H-pyrazol-5-yl)quinoline-2,4-diamine (30 mg, 0.056mmol) (assumed to be 50% HCl by weight) in DMF (0.4 mL) was addeddimethylcarbamoyl chloride (7.71 μl, 0.084 mmol). After 1.5 hours,dimethylcarbamoyl chloride (7.71 μl, 0.084 mmol) was added. After afurther 1.5 hours, dimethylcarbamoyl chloride (7.71 μl, 0.084 mmol) wasadded, and the reaction was stirred overnight. Triethylamine (0.078 mL,0.559 mmol) was added. After 2 hours, the reaction was quenched withMeOH, filtered through a syringe filter, and the crude material waspurified via preparative LC/MS with the following conditions: Column:XBridge C18, 200 mm×19 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: a 0-minutehold at 0% B, 0-40% B over 20 minutes, then a 4-minute hold at 100% B;Flow Rate: 20 mL/min; Column Temperature: 25° C. Fraction collection wastriggered by UV signals. Fractions containing the desired product werecombined and dried via centrifugal evaporation. The material was furtherpurified via preparative LC/MS with the following conditions: Column:XBridge C18, 200 mm×19 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: a 0-minutehold at 0% B, 0-40% B over 20 minutes, then a 4-minute hold at 100% B;Flow Rate: 20 mL/min; Column Temperature: 25° C. Fraction collection wastriggered by MS and UV signals. Fractions containing the desired productwere combined and dried via centrifugal evaporation to give3-(2-((2-amino-7-(1H-pyrazol-5-yl)quinolin-4-yl)amino)ethyl)-1,1-dimethylurea(8.7 mg, 45.9%). ¹H NMR (500 MHz, DMSO-d₆) δ 7.91 (br d, J=8.5 Hz, 1H),7.82-7.66 (m, 2H), 7.60 (br d, J=7.6 Hz, 1H), 7.34 (br s, 1H), 6.80 (s,2H), 6.69-6.57 (m, 1H), 5.73 (s, 1H), 3.36 (br d, J=5.5 Hz, 2H),3.26-3.16 (m, 2H), 2.80 (s, 6H). LC RT: 0.96 min. M/Z=340.22.

Example II-15: Synthesis of 4-diaminopropane Substituted Quinolines

Step 1: Preparation of tert-butyl(3-((2-amino-7-bromoquinolin-4-yl)amino)propyl)carbamate

To a solution of 7-bromo-4-chloroquinolin-2-amine (520 mg, 2.019 mmol)and tert-butyl (3-aminopropyl)carbamate (1759 mg, 10.10 mmol) in DMSO (5mL) was added Hunig's Base (1.058 mL, 6.06 mmol). The reaction washeated to 120° C. overnight. The reaction was partitioned between DCMand water. The organic layer was dried sodium sulfate and evaporated.The residue was purified via ISCO (40 g column; DCM/EtOAc; 0 to 100%gradient) to give tert-butyl(3-((2-amino-7-bromoquinolin-4-yl)amino)propyl)carbamate (478 mg, 1.20mmol, 60% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 7.86 (d, J=8.8 Hz, 1H),7.43 (d, J=2.0 Hz, 1H), 7.15 (dd, J=8.7, 2.0 Hz, 1H), 6.89 (br t, J=5.3Hz, 1H), 6.72 (br t, J=5.0 Hz, 1H), 6.12 (s, 2H), 5.71 (s, 1H),3.21-3.11 (m, 2H), 3.10-2.97 (m, 2H), 1.85-1.70 (m, 2H), 1.38 (s, 9H).

Step 2: Preparation of tert-butyl(3-((2-amino-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)quinolin-4-yl)amino)propyl)carbamate

A two phase solution of1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(420 mg, 1.512 mmol), tert-butyl(3-((2-amino-7-bromoquinolin-4-yl)amino)propyl)carbamate (478 mg, 1.209mmol), PdCl₂(dppf)-DCM adduct (99 mg, 0.121 mmol), and tripotassiumphosphate (2M aqueous) (1.814 mL, 3.63 mmol) in dioxane (10 mL) washeated to 110° C. overnight. The reaction mixture was diluted with 100ml DCM, dried with sodium sulfate and evaporated under reduced pressure.The residue was purified via ISCO (40 g column; DCM/MeOH;0 to 25%gradient) to give tert-butyl(3-((2-amino-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)quinolin-4-yl)amino)propyl)carbamate(400 mg, 0.85 mmol, 71% yield). LC/MS conditions: Column: Aquity UPLCBEH C18, 2.1 mm×50 mm, 1.7 μm particles; Mobile Phase A: 100% water with0.05% TFA; Mobile Phase B: 100% acetonitrile with 0.05% TFA; Gradient:2% B to 98% B over 1 min, then a 0.50 min hold at 100% B; Flow: 0.8mL/min. LC RT: 0.77 min. M/Z=467.

Step 3: Preparation ofN4-(3-aminopropyl)-7-(1H-pyrazol-5-yl)quinoline-2,4-diamine, 3 HCl

To a solution of tert-butyl(3-((2-amino-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)quinolin-4-yl)amino)propyl)carbamate(400 mg, 0.857 mmol) in dioxane (10 mL) was added HCl (4M in dioxane) (4mL, 16.00 mmol). After 2 hours, the reaction was evaporated under highvacuum to giveN4-(3-aminopropyl)-7-(1H-pyrazol-5-yl)quinoline-2,4-diamine, 3 HCl (336mg, 0.85 mmol, 100% yield). LC/MS conditions: Column: Aquity UPLC BEHC18, 2.1 mm×50 mm, 1.7 μm particles; Mobile Phase A: 100% water with0.05% TFA; Mobile Phase B: 100% acetonitrile with 0.05% TFA; Gradient:2% B to 98% B over 1 min, then a 0.50 min hold at 100% B; Flow: 0.8mL/min. LC RT: 0.45 min. M/Z=283.

Step 4: Preparation ofN-(3-((2-amino-7-(1H-pyrazol-5-yl)quinolin-4-yl)amino)propyl)-1-methyl-1H-imidazole-2-carboxamide,2TFA (Compound 209)

To a solution ofN4-(3-aminopropyl)-7-(1H-pyrazol-5-yl)quinoline-2,4-diamine, 3 HCl (30mg, 0.077 mmol) and 1-methyl-1H-imidazole-2-carboxylic acid (19.32 mg,0.153 mmol) and triethylamine (0.213 mL, 1.532 mmol) in DMF (1 mL) wasadded T3P (50% in DMF) (97 mg, 0.153 mmol). After stirring the reactionat room temperature overnight the reaction was concentrated under highvacuum. The reaction was diluted with 1 ml of a mixture of 1:1DMF:acetic acid and filtered through a syringe filter and purified viapreparative LC/MS with the following conditions: Column: XBridge C18,200 mm×19 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:waterwith 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:waterwith 0.1% trifluoroacetic acid; Gradient: a 5-minute hold at 0% B, 0-33%B over 25 minutes, then a 5-minute hold at 100% B; Flow Rate: 20 mL/min;Column Temperature: 25° C. Fraction collection was triggered by MSsignals. Fractions containing the desired product were combined anddried via centrifugal evaporation to giveN-(3-((2-amino-7-(1H-pyrazol-5-yl)quinolin-4-yl)amino)propyl)-1-methyl-1H-imidazole-2-carboxamideas the bis-trifluoroacetate salt (7.1 mg, 15%). ¹H NMR (500 MHz,DMSO-d₆) δ 8.44 (br s, 1H), 8.22 (br d, J=8.7 Hz, 1H), 8.02 (br s, 1H),7.93 (br s, 1H), 7.90-7.76 (m, 3H), 7.55 (br s, 1H), 7.30 (s, 1H), 6.99(s, 1H), 6.87-6.80 (m, 1H), 5.85 (s, 1H), 3.94 (s, 3H), 2.01-1.93 (m,2H). Four protons from sidechain missing, likely due to overlap withsuppressed water peak. LC RT: 1.01 min. M/Z=391.1.

Compound 210 to Compound 212 were prepared according to the syntheticprocedures described for Compound 209 from the appropriate startingmaterials.

Compd. LC/MS RT ¹H NMR No. Structure [M + H]⁺ (min) (500 MHz, DMSO-d₆)210

422.1 1.21 δ 8.40-8.29 (m, 1H), 8.00 (br d, J = 8.9 Hz, 1H), 7.81 (br s,1H), 7.74 (br s, 1H), 7.58 (br d, J = 7.9 Hz, 1H), 7.15-7.03 (m, 1H),6.92-6.79 (m, 1H), 6.76 (s, 1H), 5.72 (s, 1H), 3.25 (br d, J = 5.8 Hz,1H), 2.68 (s, 3H), 2.59 (s, 3H), 1.96-1.83 (m, 2H). Three protons fromsidechain are not visible, possibly due to overlap with suppressed waterpeak. 211

388.1 1.02 δ 8.77 (br s, 1H), 8.74-8.69 (m, 2H), 8.24 (br d, J = 8.6 Hz,1H), 8.02 (br s, 1H), 7.99-7.91 (m, 2H), 7.87-7.79 (m, 2H), 7.79-7.72(m, 2H), 7.72-7.52 (m, 1H), 6.83 (d, J = 1.9 Hz, 1H), 5.86 (s, 1H), 2.02(br t, J = 6.7 Hz, 2H). Four protons from sidechain are not visible,likely due to overlap with suppressed water peak. 212

388.1 0.95 δ 8.99 (s, 1H, 8.75-8.63 (m, 2H), 8.26-8.14 (m, 2H), 8.01 (brs, 1H), 7.93 (br d, J = 11.6 Hz, 1H), 7.84-7.74 (m, 2H), 7.50 (br dd, J= 7.8, 4.9 Hz, 2H), 6.82 (d, J = 1.9 Hz, 1H), 5.85 (s, 1H), 2.00 (quin,J = 6.7 Hz, 2H). Four protons from sidechain are not visible, likely dueto overlap with suppressed water peak.

Example II-16: Synthesis ofN-(3-((2-amino-7-(1H-pyrazol-5-yl)quinolin-4-yl)amino)propyl)acetamide,2TFA (Compound 213)

To a solution ofN4-(3-aminopropyl)-7-(1H-pyrazol-5-yl)quinoline-2,4-diamine, 3 HCl (30mg, 0.077 mmol) and triethylamine (0.213 mL, 1.532 mmol) in THF (1 mL)was added acetyl chloride (0.016 mL, 0.230 mmol). After stirring thereaction at room temperature overnight, the reaction was concentratedunder high vacuum. The reaction was diluted with a mixture of 1:1DMF:acetic acid, filtered through a syringe filter, and purified viapreparative LC/MS with the following conditions: Column: XBridge C18,200 mm×19 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:waterwith 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:waterwith 10-mM ammonium acetate; Gradient: a 3-minute hold at 0% B, 0-33% Bover 23 minutes, then a 5-minute hold at 100% B; Flow Rate: 20 mL/min;Column Temperature: 25° C. Fraction collection was triggered by MSsignals. Fractions containing the desired product were combined anddried via centrifugal evaporation to giveN-(3-((2-amino-7-(1H-pyrazol-5-yl)quinolin-4-yl)amino)propyl)acetamideas the bis-trifluoroacetate salt (17.5 mg, 52%). ¹H NMR (500 MHz,DMSO-d₆) δ 8.01-7.89 (m, 2H), 7.74 (br s, 2H), 7.55-7.44 (m, 1H), 6.80(br s, 1H), 6.75 (br s, 1H), 6.30 (br s, 1H), 5.70 (s, 1H), 3.23-3.11(m, 2H), 1.84-1.73 (m, 5H). Two protons from sidechain are not visible,likely due to overlap with suppressed water peak. LC/MS conditions:Column: Waters XBridge C18, 2.1 mm×50 mm, 1.7 μm particles; Mobile PhaseA: 5:95 acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B:95:5 acetonitrile:water with 10 mM ammonium acetate; Temperature: 50°C.; Gradient: 0% B to 100% B over 3 min, then a 0.50 min hold at 100% B;Flow: 1 mL/min. RT: 0.91 min. M/Z=325.1.

Example II-17: Synthesis of3-(3-((2-amino-7-(1H-pyrazol-5-yl)quinolin-4-yl)amino)propyl)-1,1-dimethylurea,2TFA (Compound 214)

To a solution ofN4-(3-aminopropyl)-7-(1H-pyrazol-5-yl)quinoline-2,4-diamine, 3 HCl (30mg, 0.077 mmol) and triethylamine (0.213 mL, 1.532 mmol) in DMF (1 mL)was added dimethylcarbamoyl chloride (0.021 mL, 0.230 mmol). Afterstirring the reaction at room temperature overnight, the reaction wasconcentrated under high vacuum. The reaction was diluted with a mixtureof 1:1 DMF:acetic acid, filtered through a syringe filter, and purifiedvia preparative LC/MS with the following conditions: Column: XBridgeC18, 200 mm×19 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: a 0-minutehold at 0% B, 0-40% B over 25 minutes, then a 4-minute hold at 100% B;Flow Rate: 20 mL/min; Column Temperature: 25° C. Fraction collection wastriggered by MS and UV signals. Fractions containing the desired productwere combined and dried via centrifugal evaporation to give3-(3-((2-amino-7-(1H-pyrazol-5-yl)quinolin-4-yl)amino)propyl)-1,1-dimethylureaas the bis-trifluoroacetate salt (7.8 mg, 18%). ¹H NMR (500 MHz,DMSO-d₆) δ 8.00 (br d, J=8.2 Hz, 1H), 7.78 (br s, 1H), 7.76-7.67 (m,1H), 7.58 (br s, 1H), 7.06 (br s, 1H), 6.77 (br s, 2H), 6.35 (br s, 1H),5.70 (br s, 1H), 3.20 (br s, 2H), 3.18-3.06 (m, 2H), 2.54 (br d, J=1.5Hz, 6H), 1.80 (br s, 2H). LC/MS conditions: Column: Waters XBridge C18,2.1 mm×50 mm, 1.7 μm particles; Mobile Phase A: 5:95 acetonitrile:waterwith 10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:waterwith 10 mM ammonium acetate; Temperature: 50° C.; Gradient: 0% B to 100%B over 3 min, then a 0.50 min hold at 100% B; Flow: 1 mL/min. LC RT:0.96 min. M/Z=354.1.

Example II-18: Preparation ofN-(3-((2-amino-7-(1H-pyrazol-5-yl)quinolin-4-yl)amino)propyl)methanesulfonamide(Compound 215)

To a solution ofN4-(3-aminopropyl)-7-(1H-pyrazol-5-yl)quinoline-2,4-diamine, 3 HCl (30mg, 0.077 mmol) and triethylamine (0.213 mL, 1.532 mmol) in DMF (1 mL)was added Ms-Cl (0.018 mL, 0.230 mmol). After stirring the reaction atroom temperature overnight, the reaction was concentrated under highvacuum. The reaction was diluted with a mixture of 1:1 DMF:acetic acid,filtered through a syringe filter, and purified via preparative LC/MSwith the following conditions: Column: XBridge C18, 200 mm×19 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammoniumacetate; Gradient: a 0-minute hold at 0% B, 0-40% B over 24 minutes,then a 4-minute hold at 100% B; Flow Rate: 20 mL/min; ColumnTemperature: 25° C. Fraction collection was triggered by MS and UVsignals. Fractions containing the desired product were combined anddried via centrifugal evaporation to giveN-(3-((2-amino-7-(1H-pyrazol-5-yl)quinolin-4-yl)amino)propyl)methanesulfonamideas the bis-trifluoroacetate salt (7.2 mg, 15%). ¹H NMR (500 MHz,DMSO-d₆) δ 8.04-7.91 (m, 1H), 7.75 (br s, 2H), 7.54 (br s, 1H),7.12-7.02 (m, 1H), 6.93-6.66 (m, 2H), 6.55-6.19 (m, 1H), 5.72 (s, 1H),3.32-3.19 (m, 1H), 3.19-3.04 (m, 2H), 2.95-2.86 (m, 3H), 1.89 (s, 2H).One proton from sidechain is not visible, likely due to overlap withsuppressed water peak. LC/MS conditions: Column: Waters XBridge C18, 2.1mm×50 mm, 1.7 μm particles; Mobile Phase A: 5:95 acetonitrile:water with10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10mM ammonium acetate; Temperature: 50° C.; Gradient: 0% B to 100% B over3 min, then a 0.50 min hold at 100% B; Flow: 1 mL/min. LC RT: 0.89 min.M/Z=361.1.

Example II-19: Synthesis of3-(2-amino-7-(1H-pyrazol-1-yl)quinolin-4-yl)propan-1-ol (Compound 216)

Step 1. 7-bromoquinolin-4-yl trifluoromethanesulfonate

Into a 1000-mL round-bottom flask, was placed 7-bromoquinolin-4-ol (22.4g, 99.98 mmol, 1 equiv), Hunig's base (3.8 g, 299.93 mmol, 3 equiv), andDMAP (1.2 g, 10.00 mmol, 0.100 equiv) in DMF (1000 mL, 6.84 mmol, 0.068equiv), then trifluoromethanesulfonyl chloride (25.3 g, 150 mmol, 1.502equiv) was added. The resulting solution was stirred for 16 hours atroom temperature in a water/ice bath. The resulting solution was dilutedwith 1.5 L of ethyl acetate. The resulting mixture was washed with 2×500ml of water and 2×500 ml of brine. The mixture was dried over anhydroussodium sulfate and concentrated. The resulting mixture was concentrated.The residue was applied onto a silica gel column with ethylacetate/petroleum ether (1:5). This resulted in 20 g (56.18%) of7-bromoquinolin-4-yl trifluoromethanesulfonate as a yellow solid. LC-MS:(ES, m/z): [M+H]⁺=355.9.

Step 2. 4-[3-(benzyloxy)prop-1-yn-1-yl]-7-bromoquinoline

In a 1000-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen was placed 7-bromoquinolin-4-yltrifluoromethanesulfonate (10 g, 28.08 mmol, 1 equiv) in THF (280 ml),then Hunig's base (10.9 g, 84.24 mmol, 3 equiv), CuI (1.1 g, 5.62 mmol,0.2 equiv), [(prop-2-yn-1-yloxy)methyl]benzene(6.2 g, 42.12 mmol, 1.5equiv), Pd(PPh₃)₄ (3.2 g, 0.1 equiv) were added. The resulting solutionwas stirred for 16 hours at 70° C. in an oil bath. The resulting mixturewas concentrated. The residue was applied onto a silica gel column withethyl acetate/petroleum ether (1:5). This resulted in 6 g (60.66%) of4-[3-(benzyloxy)prop-1-yn-1-yl]-7-bromoquinoline as a yellow solid.LC-MS: (ES, m/z): [M+H]⁺=352.0.

Step 3. 4-[3-(benzyloxy)propyl]-7-bromoquinoline

In a 500-mL round-bottom flask was placed4-[3-(benzyloxy)prop-1-yn-1-yl]-7-bromoquinoline (6 g, 17.03 mmol, 1equiv), and PtO₂ (0.56 g, 2.64 mmol, 0.155 equiv) in acetonitrile (170mL). The resulting solution was stirred for 16 hours at room temperatureunder H₂. The solids were filtered off. The filtrate was concentrated.The residue was applied onto a silica gel column with ethylacetate/petroleum ether (1:5). This resulted in 4.8 g (79.09%) of4-[3-(benzyloxy)propyl]-7-bromoquinoline as a yellow solid. LC-MS: (ES,m/z): [M+H]⁺=356.1.

Step 4. 4-[3-(benzyloxy)propyl]-7-(1H-pyrazol-1-yl)quinoline

In a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen was placed4-[3-(benzyloxy)propyl]-7-bromoquinoline (1 g, 2.81 mmol, 1 equiv),1H-pyrazole (955.5 mg, 14.03 mmol, 5 equiv), K₃PO₄ (1.2 g, 5.61 mmol, 2equiv), CuI (106.9 mg, 0.56 mmol, 0.2 equiv), and(1S,2S)-cyclohexane-1,2-diamine (32.1 mg, 0.28 mmol, 0.1 equiv) indioxane (28 mL, 0.32 mmol, 0.113 equiv). The resulting solution wasstirred for 5 days at 100° C. in an oil bath. The solids were filteredoff. The resulting mixture was concentrated. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (1:1). Thisresulted in 370 mg (38.38%) of4-[3-(benzyloxy)propyl]-7-(1H-pyrazol-1-yl)quinoline as a yellow solid.LC-MS: (ES, m/z): [M+H]⁺=344.2.

Step 5.4-[3-(benzyloxy)propyl]-7-(1H-pyrazol-1-yl)quinolin-1-ium-1-olate

In a 50-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed4-[3-(benzyloxy)propyl]-7-(1H-pyrazol-1-yl)quinoline (300 mg, 0.87 mmol,1 equiv) in DCM (10 mL), then m-CPBA (226.1 mg, 1.31 mmol, 1.5 equiv)was added. The resulting solution was stirred for 12 hours at roomtemperature. The reaction was then quenched by the addition of 10 mL ofNa₂S₂O₄. The pH value of the solution was adjusted to 10 with NaHCO₃.The resulting solution was extracted with 3×10 ml of dichloromethane.The resulting mixture was washed with 1×10 ml of brine. The resultingmixture was concentrated. The residue was applied onto a silica gelcolumn with dichloromethane/methanol (10:1). This resulted in 200 mg(63.70%) of4-[3-(benzyloxy)propyl]-7-(1H-pyrazol-1-yl)quinolin-1-ium-1-olate as ayellow solid. LC-MS: (ES, m/z): [M+H]⁺=360.2.

Step 6. 4-[3-(benzyloxy)propyl]-7-(1H-pyrazol-1-yl)quinolin-2-amine

Into a 50-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed4-[3-(benzyloxy)propyl]-7-(1H-pyrazol-1-yl)quinolin-1-ium-1-olate (150mg, 0.42 mmol, 1 equiv) in DCM (2 mL, 0.02 mmol) and NH₄OH (1 mL), thenTsCl (159.1 mg, 0.83 mmol, 2 equiv) was added. The resulting solutionwas stirred for 20 minutes at room temperature. The resulting mixturewas concentrated. The residue was applied onto a silica gel column withdichloromethane/methanol (10:1). This resulted in 100 mg (66.85%) of4-[3-(benzyloxy)propyl]-7-(1H-pyrazol-1-yl)quinolin-2-amine as a yellowsolid. LC-MS: (ES, m/z): [M+H]⁺=359.2.

Step 7. 3-[2-amino-7-(1H-pyrazol-1-yl)quinolin-4-yl]propan-1-ol(Compound 216)

In a 50-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed4-[3-(benzyloxy)propyl]-7-(1H-pyrazol-1-yl)quinolin-2-amine (100 mg,0.28 mmol, 1 equiv) in concentrated HCl (6 mL, 0.16 mmol, 0.590 equiv).The resulting solution was stirred for 2 hours at 40° C. The pH value ofthe solution was adjusted to 10 with ammonium hydroxide. The resultingmixture was concentrated. The crude product was purified byFlash-Prep-HPLC with the following conditions: Flash Column, C18spherical, 20-35 um, 100A, 20 g; mobile phase, Water (10 mmol/L NH₄HCO₃)and MeCN (15% Phase B up to 75% in 9 min); Detector, 254/210 nm UV. Thisresulted in 46 mg (61.45%) of3-[2-amino-7-(1H-pyrazol-1-yl)quinolin-4-yl]propan-1-ol as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.62 (d, J=2.5 Hz, 1H), 7.92 (d,J=8.9 Hz, 1H), 7.84 (d, J=2.2 Hz, 1H), 7.78 (d, J=1.7 Hz, 1H), 7.70 (dd,J=8.9, 2.3 Hz, 1H), 6.64-6.51 (m, 2H), 6.48 (s, 2H), 4.60 (t, J=5.2 Hz,1H), 3.53 (q, J=6.0 Hz, 2H), 2.97-2.89 (m, 2H), 1.86-1.75 (m, 2H). LCMethods: Column: Kinetex EVO, 3.0 mm×50 mm, 2.6 μm particles; MobilePhase A: water with 0.03% NH₄OH; Mobile Phase B: acetonitrile;Temperature: 40° C.; Gradient: 10% B to 95% B over 1.9 min, then a 0.6min hold at 95% B; Flow: 1.2 mL/min. LC retention time: 0.981 min.LC-MS: (ES, nm/z): [M+H]⁺=269.1.

Example II-20: Synthesis ofN-(2-(2-amino-7-(1H-pyrazol-5-yl)quinolin-4-yl)ethyl)acetamide (Compound217)

Step 1. benzyl N-[2-(7-bromoquinolin-4-yl)ethyl]carbamate

In a 500-ml, 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen was placed 7-bromoquinolin-4-yltrifluoromethanesulfonate (7.5 g, 21.06 mmol, 1 equiv), Cs₂CO₃ (20585.8mg, 63.18 mmol, 3.0 equiv), (2-[[(benzyloxy)carbonyl]amino]ethyl)boronicacid (9394.4 mg, 42.12 mmol, 2 equiv), and Pd(dppf)Cl₂ (1541.0 mg, 2.11mmol, 0.1 equiv) in toluene (200 mL) and 1H₂O (50 mL). The resultingsolution was stirred for 16 hours at 70° C. The resulting mixture wascooled to room temperature and concentrated. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (1:1). Thisresulted in 3.5 g (43.14%) of benzylN-[2-(7-bromoquinolin-4-yl)ethyl]carbamate as a white solid. LC-MS:[M+H]⁺=385.0.

Step 2. benzyl N-[2-[7-(1H-pyrazol-3-yl)quinolin-4-yl]ethyl]carbamate

In a 500-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed benzylN-[2-(7-bromoquinolin-4-yl)ethyl]carbamate (2 g, 5.19 mmol, 1 equiv),3-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1007.3 mg, 5.19mmol, 1.0 equiv), Pd(PPh₃)₄ (599.9 mg, 0.52 mmol, 0.1 equiv), and Na₂CO₃(1100.5 mg, 10.38 mmol, 2.0 equiv) in dioxane (80 mL, 944.33 mmol,181.903 equiv) and H₂O (20 mL, 1110.17 mmol, 213.848 equiv). Theresulting solution was stirred for 16 hours at room temperature in anoil bath. The resulting mixture was cooled to room temperature andconcentrated. The residue was applied onto a silica gel column withdichloromethane/methanol (10:1). This resulted in 1.8 g (93.10%) ofbenzyl N-[2-[7-(1H-pyrazol-3-yl)quinolin-4-yl]ethyl]carbamate as anoff-white solid. LC-MS: [M+H]⁺=373.2.

Step 3.4-(2-[[(benzyloxy)carbonyl]amino]ethyl)-7-(1H-pyrazol-3-yl)quinolin-1-ium-1-olate

In a 100-mL round-bottom flask, was placed benzylN-[2-[7-(1H-pyrazol-3-yl)quinolin-4-yl]ethyl]carbamate (1.7 g, 4.56mmol, 1 equiv) in DCM (50 mL, 0.59 mmol, 0.129 equiv), then m-CPBA(1575.4 mg, 9.13 mmol, 2.0 equiv) was added. The resulting solution wasstirred for 16 hours at room temperature. The reaction was then quenchedby the addition of 50 mL of saturated aqueous Na₂S₂O₃ solution. Theresulting solution was extracted with 3×50 ml of dichloromethane and thecombined organic layers were concentrated. The residue was applied ontoa silica gel column with dichloromethane/methanol (10:1). This resultedin 1.4 g (78.96%) of4-(2-[[(benzyloxy)carbonyl]amino]ethyl)-7-(1H-pyrazol-3-yl)quinolin-1-ium-1-olateas a solid. LC-MS: [M+H]⁺=389.2.

Step 4. benzylN-[2-[2-amino-7-(1H-pyrazol-3-yl)quinolin-4-yl]ethyl]carbamate

In a 25-mL round-bottom flask, was placed4-(2-[[(benzyloxy)carbonyl]amino]ethyl)-7-(1H-pyrazol-3-yl)quinolin-1-ium-1-olate(100 mg, 0.26 mmol, 1 equiv) in DCM (4 mL) and NH₄OH (2 mL). TsCl (97.8mg, 0.51 mmol, 2.0 equiv) was added. The resulting solution was stirredfor 2 hours at room temperature. The reaction was then quenched by theaddition of 10 mL of MeOH. The resulting mixture was concentrated. Thecrude product was purified by Prep-HPLC with the following conditions:Column, XBridge Shield RP18 OBD Column, 19*250 mm, 10 um; mobile phase,Water (10 mmol/L NH₄HCO₃) and MeCN (30% Phase B up to 47% in 10 min);Detector, 254/210 nm UV. This resulted in 39.4 mg (39.50%) of benzylN-[2-[2-amino-7-(1H-pyrazol-3-yl)quinolin-4-yl]ethyl]carbamate as awhite solid. ¹H-NMR: (300 MHz, DMSO-d₆) δ 7.87-7.63 (m, 5H), 7.46-7.27(m, 5H), 6.77 (s, 1H), 6.57 (s, 1H), 6.31 (s, 2H), 5.02 (s, 2H), 3.29(m, 2H), 3.03-2.98 (m, 2H). LC Methods: Column: Kinetex EVO, 3.0 mm×50mm, 2.6 μm particles; Mobile Phase A: water with 0.03% NH₄OH; MobilePhase B: acetonitrile; Temperature: 40° C.; Gradient: 10% B to 95% Bover 1.9 min, then a 0.60 min hold at 95% B; Flow: 1.2 mL/min. LCretention time: 1.291 min. LC-MS: [M+H]⁺=388.2.

Step 5. 4-(2-aminoethyl)-7-(1H-pyrazol-3-yl)quinolin-2-amine

In a 25-mL round-bottom flask was placed benzylN-[2-[2-amino-7-(1H-pyrazol-3-yl)quinolin-4-yl]ethyl]carbamate (50 mg,0.13 mmol, 1 equiv) in MeOH (3 mL, 0.09 mmol, 0.725 equiv), then Pd/C(15 mg, 0.14 mmol, 1.092 equiv) was added. The resulting solution wasstirred for 16 hours at room temperature under N₂. The solids werefiltered off. The resulting mixture was concentrated. The crude productwas purified by Prep-HPLC with the following conditions: Column, XBridgeShield RP18 OBD Column, 19*250 mm, 10 um; mobile phase, Water (10 mmol/LNH₄HCO₃) and MeCN (10% Phase B up to 20% in 6 min); Detector, 254/210 nmUV. This resulted in 14 mg (42.83%) of4-(2-aminoethyl)-7-(1H-pyrazol-3-yl)quinolin-2-amine as a white solid.LC Methods: Column: Kinetex EVO, 3.0 mm×50 mm, 2.6 μm particles; MobilePhase A: water with 0.03% NH₃H₂O; Mobile Phase B: acetonitrile;Temperature: 40° C.; Gradient: 10% B to 40% B over 2.49 min, 40% B to95% B over 0.9 min, then a 0.75 min hold at 95% B; Flow: 1.2 mL/min. LCretention time: 1.338 min. LC-MS: [M+H]⁺=254.1. H-NMR: (400 MHz,DMSO-d₄) S 7.89-7.84 (m, 2H), 7.72 (s, 1H), 7.62 (d, J=8 Hz, 1H),6.84-6.78 (m, 1H), 6.58 (s, 1H), 6.33 (d, J=4 Hz, 1H), 3.99-3.37 (m,1H), 3.02-2.87 (m, 3H), 1.72-1.64 (m, 2H), 1.58-1.52 (m, 2H).

Step 6. N-[2-[2-amino-7-(1H-pyrazol-3-yl)quinolin-4-yl]ethyl]acetamide(Compound 217)

In a 25-mL round-bottom flask, was placed4-(2-aminoethyl)-7-(1H-pyrazol-3-yl)quinolin-2-amine (50 mg, 0.20 mmol,1 equiv) in DCM (3 mL, 0.04 mmol, 0.179 equiv), then (CH₃CO)₂O (20.2 mg,0.20 mmol, 1.0 equiv) and Hunig's base (76.5 mg, 0.59 mmol, 3.0 equiv)were added. The resulting solution was stirred for 2 hours at roomtemperature. The reaction was then quenched by the addition of 5 mL ofMeOH. The resulting mixture was concentrated. The crude product waspurified by Prep-HPLC with the following conditions: Column, XBridgeShield RP18 OBD Column, 19*250 mm, 10 um; mobile phase, Water (10 mmol/LNH₄HCO₃) and MeCN (12% PhaseB up to 35% in 6 min); Detector, 254/210 nmUV. This resulted in 12.7 mg (21.78%) ofN-[2-[2-amino-7-(1H-pyrazol-3-yl)quinolin-4-yl]ethyl]acetamide as asolid. H-NMR: (300 MHz, DMSO-d₆) δ 8.06-8.02 (m, 1H), 7.90-7.86 (m, 2H),7.74-7.65 (m, 2H), 6.80 (s, 1H), 6.58 (s, 1H), 6.34 (s, 2H), 3.38-3.32(m, 2H), 3.03-2.98 (m, 2H), 1.82 (s, 3H). LC Methods: Column: KinetexEVO, 3.0 mm×50 mm, 2.6 μm particles; Mobile Phase A: water with 0.03%NH₄OH; Mobile Phase B: acetonitrile; Temperature: 40° C.; Gradient: 10%B to 95% B over 1.9 min, then a 0.15 min hold at 95% B; Flow: 1.2mL/min. LC retention time: 0.851 min. LC-MS: [M+H]⁺=296.1.

Example II-21: Preparation of4-(2-amino-7-(1H-pyrazol-5-yl)quinolin-4-yl)butan-1-ol (Compound 218)

Step 1. 4-[7-(1H-pyrazol-3-yl)quinolin-4-yl]but-3-yn-1-ol

In a 40-mL sealed tube was placed a solution of4-bromo-7-(1H-pyrazol-3-yl)quinoline (1.2 g, 4.38 mmol, 1.00 equiv) intetrahydrofuran (20 mL). Pd(PPh₃)₄ (500 mg, 0.43 mmol, 0.10 equiv), CuI(166 mg, 0.87 mmol, 0.20 equiv), DIPEA (1.7 g, 13.15 mmol, 3.00 equiv)and but-3-yn-1-ol (620 mg, 8.85 mmol, 2.00 equiv) were added. Theresulting solution was stirred for 16 h at 70° C. in an oil bath. Theresulting mixture was cooled to room temperature and concentrated undervacuum. The residue was applied onto a silica gel column withdichloromethane/methanol (0-10%). This resulted in 500 mg (43%) of4-[7-(1H-pyrazol-3-yl)quinolin-4-yl]but-3-yn-1-ol as a brown crudesolid. LC-MS: (ES, m/z): [M+H]⁺=264.1.

Step 2.4-[4-[(tert-butyldimethylsilyl)oxy]but-1-yn-1-yl]-7-(1H-pyrazol-3-yl)quinoline

In a 250-mL round-bottom flask was placed a solution of4-[7-(1H-pyrazol-3-yl)quinolin-4-yl]but-3-yn-1-ol (500 mg, 1.90 mmol,1.00 equiv) in dichloromethane (100 mL), TBSCl (1.45 g, 4.00 equiv),triethylamine (780 mg, 7.71 mmol, 4.00 equiv). The resulting solutionwas stirred for 2 days at 40° C. in an oil bath. The resulting mixturewas concentrated under vacuum. The residue was applied onto a silica gelcolumn with ethyl acetate: petroleum ether (1:0). This resulted in 650mg (91%) of4-[4-[(tert-butyldimethylsilyl)oxy]but-1-yn-1-yl]-7-(1H-pyrazol-3-yl)quinolineas a light-brown solid. LC-MS: (ES, m/z): [M+H]⁺=378.2.

Step 3.4-[4-[(tert-butyldimethylsilyl)oxy]butyl]-7-(1H-pyrazol-3-yl)quinoline

In a 100-mL round-bottom flask, was placed a solution of4-[4-[(tert-butyldimethylsilyl)oxy]but-1-yn-1-yl]-7-(1H-pyrazol-3-yl)quinoline(550 mg, 1.46 mmol, 1.00 equiv) in CH₃OH (30 mL). Palladium on carbon(200 mg) was added. The resulting solution was stirred for 16 hours atroom temperature under H2. The solids were filtered off. The organicmixture was concentrated and the residue was applied onto a silica gelcolumn with dichloromethane/methanol (10:1). This resulted in 350 mg(63%) of4-[4-[(tert-butyldimethylsilyl)oxy]butyl]-7-(1H-pyrazol-3-yl)quinolineas a light yellow solid. LC-MS: (ES, m/z): [M+H]⁺=382.2.

Step 4.4-[4-[(tert-butyldimethylsilyl)oxy]butyl]-7-(1H-pyrazol-3-yl)quinolin-1-ium-1-olate

In a 50-mL round-bottom flask was placed a solution of4-[4-[(tert-butyldimethylsilyl)oxy]butyl]-7-(1H-pyrazol-3-yl)quinoline(300 mg, 0.79 mmol, 1.00 equiv) in dichloromethane (20 mL), m-CPBA (270mg, 1.56 mmol, 2.00 equiv) was added. The resulting solution was stirredfor 5 hours at room temperature. The reaction was then quenched by theaddition of Na₂S₂O₃. The resulting mixture was washed with 50 mL ofsodium bicarbonate. The resulting aqueous solution was extracted with3×50 mL of dichloromethane. The organic layers were combined andconcentrated. The residue was applied onto a silica gel column withdichloromethane/methanol (10:1). This resulted in 320 mg (102%) of4-[4-[(tert-butyldimethylsilyl)oxy]butyl]-7-(1H-pyrazol-3-yl)quinolin-1-ium-1-olateas a white solid. LC-MS: (ES, m/z): [M+H]⁺=398.2.

Step 5.4-[4-[(tert-butyldimethylsilyl)oxy]butyl]-7-(1H-pyrazol-3-yl)quinolin-2-amine

Into a 50-mL round-bottom flask, was placed a solution of4-[4-[(tert-butyldimethylsilyl)oxy]butyl]-7-(1H-pyrazol-3-yl)quinolin-1-ium-1-olate(270 mg, 0.68 mmol, 1.00 equiv) in dichloromethane (15 mL) and NH₄OH (5mL). TsCl (260 mg, 2.00 equiv) was added. The resulting solution wasstirred for 2 hours at room temperature. The resulting mixture wasconcentrated under vacuum. This resulted in 240 mg (89%) of4-[4-[(tert-butyldimethylsilyl)oxy]butyl]-7-(1H-pyrazol-3-yl)quinolin-2-amineas a light yellow solid. LC-MS: (ES, m/z): [M+H]⁺=397.2.

Step 6. 4-[2-amino-7-(1H-pyrazol-3-yl)quinolin-4-yl]butan-1-ol (Compound218)

In a 50-mL round-bottom flask, was placed a solution of4-[4-[(tert-butyldimethylsilyl)oxy]butyl]-7-(1H-pyrazol-3-yl)quinolin-2-amine(200 mg, 0.50 mmol, 1.00 equiv) in hydrogen chloride in methanol (10mL). The resulting solution was stirred for 4 hours at room temperature.The pH value of the solution was adjusted to 10 with NH₄OH. Theresulting mixture was concentrated under vacuum. The crude product waspurified by Prep-HPLC with the following conditions: Column, XBridgeShield RP18 OBD Column, 19*250 mm, 10 um; mobile phase, Water (10 mmol/LNH₄HCO₃) and MeCN (10.0% MeCN up to 70.0% in 7 min); Detector, UV254/210 nm. This resulted in 101 mg (71%) of4-[2-amino-7-(1H-pyrazol-3-yl)quinolin-4-yl]butan-1-ol as a white solid.¹H-NMR: (300 MHz, DMSO-d₆) δ 13.38-12.90 (d, J=8.4 Hz, 1H), 7.85-7.55(m, 4H), 6.78 (s, 1H), 6.59 (d, J=7.2 Hz, 1H), 6.35-6.27 (d, J=24 Hz,2H), 4.42-4.39 (m, 1H), 3.48-3.42 (m, 2H), 2.90-2.85 (m, 2H), 1.72-1.64(m, 2H), 1.58-1.52 (m, 2H).

LC Methods: Column: Waters Xbridge shield RP18, 4.6 mm×50 mm, 3.5 μmparticles; Mobile Phase A: water with 0.03% NH₄OH; Mobile Phase B:acetonitrile; Temperature: 40° C.; Gradient: 10% B to 70% B over 2.4min, 70% B to 95% B over 0.7 min, then a 0.98 min hold at 95% B; Flow:1.5 mL/min. LC retention time: 1.837 min. LC-MS: (ES, m/z): [M+H]⁺=283.

Example II-22: Preparation of3-(2-amino-7-(isothiazol-3-yl)quinolin-4-yl)propan-1-ol (Compound 219)

Step 1. [4-[3-(benzyloxy)propyl]quinolin-7-yl]boronic acid

In a 100-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen was placed4-[3-(benzyloxy)propyl]-7-bromoquinoline (1 g, 2.81 mmol, 1 equiv), KOAc(551.0 mg, 5.61 mmol, 2 equiv),4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(1425.6 mg, 5.61 mmol, 2 equiv), and Pd(dppf)Cl₂ (205.4 mg, 0.28 mmol,0.1 equiv) in dioxane (20 mL). The resulting solution was stirred for 16hours at 90° C. in an oil bath. The solids were filtered off. Theresulting mixture was concentrated. This resulted in 904 mg of[4-[3-(benzyloxy)propyl]quinolin-7-yl]boronic acid as a light yellowsolid. LC-MS: (ES, m/z): [M+H]⁺=322.2.

Step 2. 4-[3-(benzyloxy)propyl]-7-(1,2-thiazol-3-yl)quinolone

In a 50-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen, was placed[4-[3-(benzyloxy)propyl]quinolin-7-yl]boronic acid (904 mg, 2.81 mmol, 1equiv), Na₂CO₃ (596.6 mg, 5.63 mmol, 2 equiv), 3-bromo-1,2-thiazole(923.3 mg, 5.63 mmol, 2 equiv), and Pd(PPh₃)₄ (325.2 mg, 0.28 mmol, 0.1equiv) in dioxane (20 mL) and H₂O (5 mL). The resulting solution wasstirred for 4 hours at 80° C. in an oil bath. The resulting mixture wascooled to room temperature and concentrated. The residue was appliedonto a silica gel column with ethyl acetate/petroleum ether (1:1). Thisresulted in 500 mg (49.28%) of4-[3-(benzyloxy)propyl]-7-(1,2-thiazol-3-yl)quinoline as a light browsolid. LC-MS: (ES, m/z): [M+H]⁺=361.1.

Step 3.4-[3-(benzyloxy)propyl]-7-(1,2-thiazol-3-yl)quinolin-1-ium-1-olate

In a 25-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed4-[3-(benzyloxy)propyl]-7-(1,2-thiazol-3-yl)quinoline (450 mg, 1.25mmol, 1 equiv) in DCM (12 mL), m-CPBA (430.9 mg, 2.50 mmol, 2 equiv) wasadded. The resulting solution was stirred for 5 hours at roomtemperature. The reaction was then quenched by the addition of Na₂S₂O₄.The pH value of the solution was adjusted to 10 with NaHCO₃. Theresulting solution was extracted with 3×20 mL of ethyl acetate andconcentrated. The residue was applied onto a silica gel column withdichloromethane/methanol (20:1). This resulted in 130 mg (27.66%) of4-[3-(benzyloxy)propyl]-7-(1,2-thiazol-3-yl)quinolin-1-ium-1-olate as alight yellow solid. LC-MS: (ES, m/z): [M+H]⁺=377.1.

Step 4. 4-[3-(benzyloxy)propyl]-7-(1,2-thiazol-3-yl)quinolin-2-amine

In a 25-mL round-bottom flask purged and maintained with an inertatmosphere of nitrogen was placed4-[3-(benzyloxy)propyl]-7-(1,2-thiazol-3-yl)quinolin-1-ium-1-olate (130mg, 0.35 mmol, 1 equiv) in DCM (3 mL) and NH₄OH (1.5 mL, 38.52 mmol).TsCl (131.7 mg, 0.69 mmol, 2 equiv) was added. The resulting solutionwas stirred for 2 hours at room temperature. The resulting mixture wasconcentrated. The residue was applied onto a silica gel column withdichloromethane/methanol (10:1). This resulted in 120 mg (92.55%) of4-[3-(benzyloxy)propyl]-7-(1,2-thiazol-3-yl)quinolin-2-amine as a lightyellow solid. LC-MS: (ES, m/z): [M+H]⁺=376.1.

Step 5. 3-(2-amino-7-(isothiazol-3-yl)quinolin-4-yl)propan-1-ol(Compound 219)

In a 25-mL round-bottom flask was placed4-[3-(benzyloxy)propyl]-7-(1,2-thiazol-3-yl)quinolin-2-amine in hydrogenchloride in MeOH (4M). The resulting solution was stirred for 16 hoursat room temperature. The pH value of the solution was adjusted to 10with NH₄OH. The resulting mixture was concentrated. The crude productwas purified by Prep-HPLC with the following conditions (Prep-HPLC-018):Column, XBridge Prep OBD C18 Column, 19*250 mm, 5 um; mobile phase,Water (10 mmol/L NH₄HCO₃) and MeCN (10% Phase B up to 50% in 7 min);Detector, UV. This resulted in 26 mg (41.91%) of3-[2-amino-7-(1,2-thiazol-3-yl)quinolin-4-yl]propan-1-ol as a whitesolid. ¹H-NMR: (400 MHz, DMSO-d₆, ppm): δ 9.19 (d, J=4.4 Hz, 1H)8.08-8.05 (m, 2H), 7.92-7.84 (m, 2H), 6.65 (s, 1H), 6.41 (s, 2H),4.63-4.60 (m, 1H), 3.55-3.50 (m, 2H), 2.95-2.92 (m, 2H), 1.83-1.79 (m,2H). LC Methods: Column: Kinetex EVO 3.0 mm×50 mm, 2.6 μm particles;Mobile Phase A: water with 0.03% NH₄OH; Mobile Phase B: acetonitrile;Temperature: 40° C.; Gradient: 10% B to 95% B over 2 min, then a 0.60min hold at 95% B; Flow: 1.2 mL/min. LC retention time: 1.073 min.LC-MS: (ES, m/z): [M+H]⁺=286.

Procedure for Compound 109:

Compound 109 was prepared following the same procedure given forCompound 110. M/Z=295.6.

Procedure for Compound 111):

Compound 111 was prepared following the same procedure given forCompound 112. ¹H NMR (400 MHz, Methanol-d₄) δ 7.95-7.84 (m, 1H), 7.80(d, J=6.1 Hz, 1H), 7.73-7.58 (m, 3H), 6.75 (br s, 1H), 3.47-3.34 (m,4H), 2.71 (br d, J=6.4 Hz, 2H), 2.10 (d, J=9.1 Hz, 3H), 1.83-1.62 (m,4H), 1.26-1.01 (m, 3H). LC/MS conditions: Column: BEH C18 2.1×50 mm, 1.7μm particles; Mobile Phase A: water with 0.05% trifluoroacetic acid;Mobile Phase B: acetonitrile with 0.05% trifluoroacetic acid;Temperature: 25° C.; Gradient: 2% B to 98% B over 1.6 min, then a 0.4min hold at 98% B; Flow: 0.8 mL/min; Detection: MS and UV (220 nm). LCRT: 0.62 min. M/Z=352.1.

Example III-1: Synthesis of(S)-3-((2-amino-7-(1H-pyrazol-5-yl)quinolin-4-yl)oxy)propane-1,2-diol

Step 1. Preparation of(S)-3-((2-amino-7-(1H-pyrazol-5-yl)quinolin-4-yl)oxy)propane-1,2-diol(Compound 220)

To a solution of (R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol (60.3 mg,0.456 mmol) and4-chloro-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)quinolin-2-amine(20 mg, 0.061 mmol) in NMP (406 μl) was added potassium tert-butoxide(17.06 mg, 0.152 mmol). The reaction was heated to 100° C. overnight.The reaction was diluted with water and extracted three times withEtOAc. The organic layers were concentrated. The residue was dissolvedin 0.4 mL DCM and 0.4 mL TFA. After 1 hour, the reaction wasconcentrated and azeotroped with DCM. The residue was dissolved in DMF,filtered through a syringe filter, and submitted to SCP purified viapreparative LC/MS with the following conditions: Column: XBridge C18,200 mm×19 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:waterwith 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:waterwith 10-mM ammonium acetate; Gradient: a 0-minute hold at 0% B, 0-40% Bover 24 minutes, then a 4-minute hold at 100% B; Flow Rate: 20 mL/min;Column Temperature: 25° C. Fraction collection was triggered by MS andUV signals. Fractions containing the desired product were combined anddried via centrifugal evaporation to give(7(S)-3-((2-amino-7-(1H-pyrazol-5-yl)quinolin-4-yl)oxy)propane-1,2-diol(7.6 mg, 41%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.10 (br d, J=8.2 Hz, 1H),8.04 (br s, 1H), 7.94-7.80 (m, 2H), 6.86 (s, 1H), 6.39 (s, 1H), 4.30 (brdd, J=9.5, 3.4 Hz, 1H), 4.17 (br dd, J=9.6, 6.3 Hz, 1H), 3.98 (br s,1H), 3.56 (br s, 1H), 3.34 (br s, 1H). LC/MS conditions: Column: WatersXBridge C18, 2.1 mm×50 mm, 1.7 μm particles; Mobile Phase A: 5:95acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10 mM ammonium acetate; Temperature: 50° C.;Gradient: 0% B to 100% B over 3 min, then a 0.50 min hold at 100% B;Flow: 1 mL/min; Detection: MS and UV (220 nm). LC RT: 0.57 min.M/Z=301.0.

Compound 221 was prepared according to the synthetic proceduresdescribed for Compound 220 from the appropriate starting materials.

¹H NMR (400 MHz, MeOH-d₄) δ 8.18 (d, J=8.5 Hz, 1H), 7.93 (s, 1H), 7.86(br d, J=8.3 Hz, 1H), 7.75 (d, J=1.7 Hz, 1H), 6.83 (d, J=2.0 Hz, 1H),6.36 (s, 1H), 4.42-4.33 (m, 1H), 4.32-4.24 (m, 1H), 4.20-4.10 (m, 1H),3.76 (d, J=5.6 Hz, 2H). LC RT: 0.84 min. M/Z=301.0.

Example III-2: Preparation of4-((1H-pyrazol-5-yl)methoxy)-7-(1H-pyrazol-5-yl)quinolin-2-amine(Compound 313)

4-((1H-pyrazol-5-yl)methoxy)-7-(1H-pyrazol-5-yl)quinolin-2-amine wasprepared from (1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)methanol(55.4 mg, 0.304 mmol) and4-chloro-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)quinolin-2-amine(20 mg, 0.061 mmol) in the same manner as described in Example II-8. ¹HNMR (500 MHz, DMSO-d6) δ 7.97-7.61 (m, 5H), 6.80 (s, 1H), 6.54-6.39 (m,2H), 5.29 (br s, 2H). LC/MS conditions: Column: Waters XBridge C18, 2.1mm×50 mm, 1.7 μm particles; Mobile Phase A: 5:95 acetonitrile:water with10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10mM ammonium acetate; Temperature: 50° C.; Gradient: 0% B to 100% B over3 min, then a 0.50 min hold at 100% B; Flow: 1 mL/min. Detection: MS andUV (220 nm). LC RT: 1.16 min. M/Z=307.3.

Example III-3: Synthesis of 7-(1H-pyrazol-5-yl)quinolin-2-amine(Compound 314)

4-Chloro-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)quinolin-2-amine(20 mg, 0.061 mmol) was dissolved in MeOH (0.75 mL) and THF (0.25 mL).The flask was briefly placed under vacuum and backfilled with nitrogentwice. Pd—C (10% on carbon, 50% wet, 3 mg, 0.028 mmol) was added, thenthe flask was fitted with a hydrogen balloon, briefly placed undervacuum, backfilled with hydrogen, and stirred overnight. The reactionwas diluted with MeOH and filtered through a syringe filter. Thefiltrate was concentrated. The residue was dissolved in 0.5 mL DCM and0.5 mL TFA. After 1 hour, the reaction was concentrated and azeotropedwith DCM. The residue was dissolved in DMF, filtered through a syringefilter, and purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 200 mm×19 mm, 5-μm particles; MobilePhase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; MobilePhase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient:a 0-minute hold at 2% B, 2-42% B over 20 minutes, then a 4-minute holdat 100% B; Flow Rate: 20 mL/min; Column Temperature: 25° C. Fractioncollection was triggered by MS and UV signals. Fractions containing thedesired product were combined and dried via centrifugal evaporation togive 7-(1H-pyrazol-5-yl)quinolin-2-amine (5.3 mg, 41%). ¹H NMR (500 MHz,DMSO-d6) δ 7.87 (d, J=8.9 Hz, 1H), 7.83 (s, 1H), 7.71 (br s, 1H),7.67-7.58 (m, 2H), 6.78 (d, J=2.1 Hz, 1H), 6.73 (d, J=8.5 Hz, 1H), 6.38(s, 1H). LC/MS conditions: Column: Waters XBridge C18, 2.1 mm×50 mm, 1.7μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mMammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mMammonium acetate; Temperature: 50° C.; Gradient: 0% B to 100% B over 3min, then a 0.50 min hold at 100% B; Flow: 1 mL/min; Detection: MS andUV (220 nm). LC RT: 0.91 min. M/Z=211.2.

Example III-4: Synthesis2-((2-amino-7-(1H-pyrazol-5-yl)quinolin-4-yl)amino)propane-1,3-diol(Compound 315)

To a solution of 2,2-dimethyl-1,3-dioxan-5-amine (39.9 mg, 0.304 mmol)and4-chloro-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)quinolin-2-amine(20 mg, 0.061 mmol) in DMSO (406 μl) was added2,2-dimethyl-1,3-dioxan-5-amine (39.9 mg, 0.304 mmol). The reaction washeated to 120° C. After 16 hours, additional2,2-dimethyl-1,3-dioxan-5-amine (39.9 mg, 0.304 mmol) and hunig's base(31.9 μl, 0.182 mmol) were added. After a further 24 hours, the reactionwas cooled, diluted with water, and extracted three times with EtOAC.The organic layers were concentrated. The residue was dissolved in 0.5mL MeOH 0.3 mL concentrated HCl was added. After 4 hours, the reactionwas concentrated and azeotroped with MeOH. The residue was dissolved inMeOH, neutralized with solid K₂CO₃, filtered through a syringe filter,and The crude material was purified via preparative LC/MS with thefollowing conditions: Column: XBridge C18, 200 mm×19 mm, 5-μm particles;Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate;Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate;Gradient: a 2-minute hold at 0% B, 0-45% B over 20 minutes, then a4-minute hold at 100% B; Flow Rate: 20 mL/min; Column Temperature: 25°C. Fraction collection was triggered by MS and UV signals. Fractionscontaining the desired product were combined and dried via centrifugalevaporation to give2-((2-amino-7-(1H-pyrazol-5-yl)quinolin-4-yl)amino)propane-1,3-diol (5.9mg, 31%). ¹H NMR (500 MHz, DMSO-d₆) δ 7.99 (br d, J=8.5 Hz, 1H), 7.93(s, 1H), 7.78 (br s, 1H), 7.76-7.70 (m, 1H), 7.62-7.55 (m, 1H), 6.79 (s,1H), 5.76 (s, 1H), 3.86-3.78 (m, 1H), 3.57-3.49 (m, 1H), 3.45 (br t,J=5.3 Hz, 1H), 3.37-3.28 (m, 1H), 3.15-3.08 (m, 1H). Column: WatersXBridge C18, 2.1 mm×50 mm, 1.7 μm particles; Mobile Phase A: 5:95acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10 mM ammonium acetate; Temperature: 50° C.;Gradient: 0% B to 100% B over 3 min, then a 0.50 min hold at 100% B;Flow: 1 mL/min; Detection: MS and UV (220 nm). LC RT: 0.61 min.M/Z=300.1.

Example III-5: Synthesis of7-(1H-pyrazol-5-yl)-N4-(pyrimidin-2-ylmethyl)quinoline-2,4-diamine(Compound 316)

Brettphos precatalyst generation 1 (4.86 mg, 6.08 μmol),4-chloro-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)quinolin-2-amine(20 mg, 0.061 mmol), and sodium tert-butoxide (14.61 mg, 0.152 mmol)were placed in a vial. The vial was placed under vacuum an backfilledwith nitrogen twice. Dioxane (0.5 mL) and pyrimidin-2-ylmethanamine(13.28 mg, 0.122 mmol) were added, nitrogen was bubbled through thesolution, and the reaction was heated to 100° C. overnight. The reactionwas cooled, diluted with water, and extracted three times with EtOAc.The organic layers were concentrated. The residue was dissolved in 0.5mL DCM and 0.5 mL TFA. After 1 hour, the reaction was concentrated andazeotroped with DCM. The residue was dissolved in DMF, filtered througha syringe filter, and the crude material was purified via preparativeLC/MS with the following conditions: Column: XBridge C18, 200 mm×19 mm,5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mMammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mMammonium acetate; Gradient: a 0-minute hold at 0% B, 0-30% B over 25minutes, then a 4-minute hold at 100% B; Flow Rate: 20 mL/min; ColumnTemperature: 25° C. Fraction collection was triggered by MS signals.Fractions containing the desired product were combined and dried viacentrifugal evaporation to give7-(1H-pyrazol-5-yl)-N4-(pyrimidin-2-ylmethyl)quinoline-2,4-diamine (4.9mg, 25%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.79 (d, J=4.9 Hz, 2H), 8.10 (d,J=8.5 Hz, 1H), 8.05-7.92 (m, 1H), 7.81 (br s, 1H), 7.78-7.72 (m, 1H),7.70-7.64 (m, 1H), 7.42 (t, J=4.9 Hz, 1H), 6.81 (d, J=1.8 Hz, 1H), 5.61(s, 1H), 4.68 (br d, J=5.8 Hz, 2H). LC/MS conditions: Column: WatersXBridge C18, 2.1 mm×50 mm, 1.7 μm particles; Mobile Phase A: 5:95acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10 mM ammonium acetate; Temperature: 50° C.;Gradient: 0% B to 100% B over 3 min, then a 0.50 min hold at 100% B;Flow: 1 mL/min; Detection: MS and UV (220 nm). LC RT: 1.01 min.M/Z=318.3,

Compound 317 was prepared according to the synthetic proceduresdescribed for Compound 316 from the appropriate starting materials.

¹H NMR (500 MHz, DMSO-d₆) δ 9.09 (s, 1H), 8.81 (s, 2H), 8.04 (br d,J=8.7 Hz, 1H), 7.79 (s, 1H), 7.77-7.71 (m, 1H), 7.68-7.60 (m, 1H),6.82-6.77 (m, 1H), 5.68 (s, 1H), 4.53 (br d, J=3.4 Hz, 2H). LC RT: 0.90min W/Z=318.2.

Example III-6: Synthesis of 6 substituted 4-aminoquinolines

Step 1. Preparation of5-(((3-bromo-4-fluorophenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-done

A solution of 3-bromo-4-fluoroaniline (1.9 g, 10.00 mmol) and5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (2.234 g, 12.00mmol) in dioxane (5 mL) was heated to 120° C. for 20 minutes. Thereaction mixture is then cooled to room temperature and diluted with 50ml of dietheyl ether. The solid was filtered and dried to give5-(((3-bromo-4-fluorophenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione(2.77 g, 8.0 mmol, 80%). ¹H NMR (400 MHz, DMSO-d₆) δ 11.23 (br d, J=14.4Hz, 1H), 8.53 (d, J=14.5 Hz, 1H), 8.06 (dd, J=6.0, 2.8 Hz, 1H),7.69-7.61 (m, 1H), 7.44 (t, J=8.7 Hz, 1H), 1.73-1.63 (m, 6H).

Step 2. Preparation of 7-bromo-6-fluoroquinolin-4-ol

A solution of5-(((3-bromo-4-fluorophenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione(2.77 g, 8.05 mmol) in phenyl ether (7 mL) is heated to 240° C. for 10minutes. The reaction mixture is then cooled to room temperature anddiluted with 50 ml of dietheyl ether. The solid was filtered and driedto give a 1:1 mixture of 7-bromo-6-fluoroquinolin-4-ol and5-bromo-6-fluoroquinolin-4-ol (0.982 g, 4.0 mmol, 50%).

Step 3. Preparation of 7-bromo-4-chloro-6-fluoroquinoline

To a suspension of a 1:1 mixture of 7-bromo-6-fluoroquinolin-4-ol and5-bromo-6-fluoroquinolin-4-ol (982 mg, 4.06 mmol) in toluene (7 mL) wasadded POCl₃ (0.756 mL, 8.11 mmol). The reaction mixture was then heatedto 100° C. for 1 hour. The cooled reaction mixture was poured over iceand then partitioned between DCM and saturated sodium carbonatesolution. The organic layer was dried with sodium sulfate andconcentrated. The residue was purified via ISCO (80 g column;Hexanes/Ethyl acetate; 0 to 100% gradient) to give7-bromo-4-chloro-6-fluoroquinoline (203 mg, 0.8 mmol, 19%). ¹H NMR (400MHz, DMSO-d₆) δ 8.88 (d, J=4.7 Hz, 1H), 8.54 (d, J=6.8 Hz, 1H), 8.09 (d,J=9.5 Hz, 1H), 7.88 (d, J=4.8 Hz, 1H)

Step 4. Preparation of 7-bromo-4-chloro-6-fluoroquinoline 1-oxide

To a solution of 7-bromo-4-chloro-6-fluoroquinoline (0.203 g, 0.779mmol) in DCM (10.0 ml) was added mCPBA (0.576 g, 2.34 mmol). Thereaction was stirred overnight, then quenched with saturated sodiumthiosulfate solution. The reaction was stirred for 0.5 hours, thensaturated aqueous sodium bicarbonate was added. The reaction wasextracted twice with DCM. The organic layers were washed with brine,dried with sodium sulfate, and concentrated to give7-bromo-4-chloro-6-fluoroquinoline 1-oxide (0.215 g, 0.779 mmol,quantitative yield). ¹H NMR (400 MHz, DMSO-d₆) δ 8.87 (d, J=6.7 Hz, 1H),8.60 (d, J=6.6 Hz, 1H), 8.13 (d, J=9.2 Hz, 1H), 7.80 (d, J=6.6 Hz, 1H).

Step 5: Preparation of 7-bromo-4-chloro-6-fluoroquinolin-2-amine

In one round-bottomed flask, 7-bromo-4-chloro-6-fluoroquinoline 1-oxide(240 mg, 0.868 mmol) was suspended in DCM (8 mL). TsCl (182 mg, 0.955mmol) was added. This mixture was stirred for one hour. In a secondround-bottomed flask, ammonium chloride (232 mg, 4.34 mmol) (dried in anoven at 110° C. overnight) was suspended in DCM (4 mL). Triethylamine(0.605 mL, 4.34 mmol) was added and the mixture was stirred for 0.5hours, then the contents of the first roundbottom flask were added tothe second. The reaction was stirred overnight, then filtered andconcentrated. The residue was purified via ISCO (24 g column;Hexanes/Ethyl acetate; 0 to 100% gradient) to give7-bromo-4-chloro-6-fluoroquinolin-2-amine (128 mg, 0.47 mmol, 54%).

Step 6: Preparation of4-chloro-6-fluoro-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)quinolin-2-amine

In a pressure vial was placed1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.174 g, 0.626 mmol), 7-bromo-4-chloroquinolin-2-amine (0.115 g, 0.417mmol), and PdCl₂(dppf)-DCM adduct (0.034 g, 0.042 mmol). The vial wasplaced under vacuum and backfilled with nitrogen three times. Dioxane(10 ml) and tripotassium phosphate (2M aqueous) (0.63 ml, 1.25 mmol)were added, nitrogen was bubbled through the solution, then the reactionwas heated to 100° C. overnight. The reaction was cooled to roomtemperature, diluted with 50 ml of ethyl acetate, dried with sodiumsulfate, and concentrated. The residue was purified via ISCO (12 gcolumn; Hexanes/Etheyl acetate; 0 to 100% gradient) to give of4-chloro-6-fluoro-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)quinolin-2-amine(0.113 g, 0.22 mmol, 52% yield).

Step 7: Preparation of3-((2-amino-6-fluoro-7-(1H-pyrazol-5-yl)quinolin-4-yl)amino)propan-1-ol(Compound 318)

To a solution of4-chloro-6-fluoro-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)quinolin-2-amine(60 mg, 0.173 mmol) and 3-aminopropan-1-ol (39 mg, 0.52 mmol) in DMSO(0.5 mL) was added Hunig's Base (0.3 mL, 1.7 mmol). The reaction washeated to 120° C. overnight. The reaction was cooled, diluted withwater, and extracted three times with DCM. The organic layers wereconcentrated, dissolved in 5 mL DCM, and 4N HCl in dioxane (1.038 mL,4.15 mmol) was added. After 20 minutes, the reaction was complete byLCMS. The reaction was concentrated. The residue was dissolved in DMF,filtered through a syringe filter, and the crude material was purifiedvia preparative LC/MS with the following conditions: Column: XBridgeC18, 200 mm×19 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: a 0-minutehold at 0% B, 0-40% B over 20 minutes, then a 4-minute hold at 100% B;Flow Rate: 20 mL/min; Column Temperature: 25° C. Fraction collection wastriggered by MS signals. Fractions containing the desired product werecombined and dried via centrifugal evaporation. The material was furtherpurified via preparative LC/MS with the following conditions: Column:XBridge C18, 200 mm×19 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: a 0-minutehold at 0% B, 0-40% B over 20 minutes, then a 4-minute hold at 100% B;Flow Rate: 20 mL/min; Column Temperature: 25° C. Fraction collection wastriggered by MS signals. Fractions containing the desired product werecombined and dried via centrifugal evaporation to give3-((2-amino-6-fluoro-7-(1H-pyrazol-5-yl)quinolin-4-yl)amino)propan-1-ol(3.7 mg, 7.1%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.19-8.13 (m, 1H), 8.11 (brs, 1H), 7.98-7.92 (m, 1H), 7.88 (br s, 1H), 7.58 (br s, 1H), 6.77 (br s,1H), 5.83 (s, 1H), 3.55 (br d, J=4.0 Hz, 2H), 3.45-3.25 (m, 2H), 1.84(quin, J=6.6 Hz, 2H) One methylene from sidechain is not visible, likelydue to overlap with suppressed water peak. LC RT: 0.80 min. M/Z=302.1

Compound 319 and Compound 320 were prepared according to the syntheticprocedures described for Compound 318 from the appropriate startingmaterials.

Compd. LC/MS RT ¹H NMR No. Structure [M + H]⁺ (min) (500 MHz, DMSO-d₆)319

298.1 0.81 δ 7.95-7.90 (m, 1H), 7.76 (br s, 1H), 7.57 (s, 1H), 7.24-7.05(m, 2H), 6.56 (s, 1H), 5.72 (s, 1H), 3.29 (br d, J = 6.1 Hz, 2H), 2.49(s, 3H), 1.87-1.79 (m, 2H).). One methylene is not visible, possibly dueto overlap with suppressed water peak. 320

314.1 0.83 δ 8.31-8.00 (m, 2H), 7.92- 7.68 (m, 2H), 7.63-7.38 (m, 2H),6.87 (br s, 1H), 5.84 (s, 1H), 3.98 (s, 3H), 3.57 (t, J = 6.1 Hz, 1H),1.91-1.82 (m, 2H). Three protons are not visible, possibly due tooverlap with suppressed water peak.

Example III-7. Preparation of(S)-7-(1H-pyrazol-3-yl)-N4-(pyrrolidin-3-yl)quinoline-2,4-diamine(Compound 321)

To a solution of4-chloro-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)quinolin-2-amine(100 mg, 0.304 mmol) in NMP (1 mL) was added tert-butyl(3S)-3-((2-amino-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)quinolin-4-yl)amino)pyrrolidine-1-carboxylateand Hunig's base (0.531 mL, 3.04 mmol). The resulted mixture was heatedto 150° C. overnight. The reaction was cooled, diluted with water, andextracted three times with EtOAc. The organic layers were concentrated.The residue was dissolved in 0.4 mL DCM and 0.4 mL TFA. After 1 hour,the THP deprotection was complete by LCMS. The reaction was concentratedand azeotroped with DCM. The residue was dissolved in DMF, filteredthrough a syringe filter, and the crude material was purified bypreparative reverse-phase HPLC with the following conditions: Column:Luna 30×100 mm 5 μM particle size; Mobile Phase A: 10:9 methanol: waterwith 0.1% trifluoroacetic acid; Mobile Phase B: 90:10 methanol: waterwith 0.1% trifluoroacetic acid; Gradient: a 0-minute hold at 0% B,0-100% B over 10 minutes, then a 2-minute hold at 100% B; Flow Rate: 40mL/min; Column Temperature: 25° C. to give(S)-7-(1H-pyrazol-3-yl)-N4-(pyrrolidin-3-yl)quinoline-2,4-diamine (55mg, 0.187 mmol, 61.4% yield). ¹H NMR (400 MHz, METHANOL-d₄) δ 8.34-8.27(m, 1H), 7.98-7.91 (m, 1H), 7.90-7.84 (m, 1H), 7.80-7.77 (m, 1H),6.94-6.83 (m, 1H), 6.02-5.89 (m, 1H), 3.75-3.64 (m, 2H), 3.35-3.30 (m,1H), 2.44-2.28 (m, 2H), 2.13-1.98 (m, 2H). LC/MS conditions: Column:Waters XBridge C18, 2.1 mm×50 mm, 1.7 μm particles; Mobile Phase A: 5:95acetonitrile:water with 10 mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10 mM ammonium acetate; Temperature: 50° C.;Gradient: 0% B to 100% B over 3 min, then a 0.50 min hold at 100% B;Flow: 1 mL/min; Detection: MS and UV (220 nm). LC RT: 0.58 min.M/Z=295.0.

Example III-8: Preparation of7-(1H-pyrazol-3-yl)-N4-(2-(thiophen-2-yl)ethyl)quinoline-2,4-diamine(Compound 322)

Step 1. Preparation of N-(7-bromo-4-chloroquinolin-2-yl)benzamide

A solution of 7-bromo-4-chloroquinoline 1-oxide (2.326 g, 9 mmol) indichloroethane (22.50 ml) was treated with benzoyl isocyanate (2.94 g,18.00 mmol), and the resulting mixture was heated to reflux for 16h. Thereaction was cooled to RT, applied to a silica gel column and elutedwith 5-25% EtOAc-hexane. (The column and mobile phase were kept warmwith a heat gun to keep product from precipitating extensively.)Concentration of the appropriate fractions affordedN-(7-bromo-4-chloroquinolin-2-yl)benzamide (2.8 g, 7.74 mmol, 86% yield)as an off-white solid, mp. 142-143° C. LCMS method: Waters Acquity SDSusing the following method: Linear Gradient of 2% to 98% solvent B over1.00 min; UV visualization at 220 or 254 nm; Column: BEH C18 2.1 mm×50mm; 1.7 um particle (Heated to Temp. 50° C.); Flow rate: 0.8 ml/min;Mobile phase A: 100% Water, 0.05% TFA; Mobile phase B: 100%Acetonitrile, 0.05% TFA. LC RT: 1.10 min. M/Z=363.0.

Step 2. Preparation of 7-bromo-4-(2-(thiophen-3-yl)ethoxy)quinoline

A solution of 2-(thiophen-2-yl)ethan-1-amine (132 mg, 1.037 mmol) andN-(7-bromo-4-chloroquinolin-2-yl)benzamide (75 mg, 0.207 mmol) in DMSO(518 μl) was heated at 120° C. for four hours then cooled to RT. Thereaction was then purified by reverse-phase prep. HPLC (MeOH-watergradient, 0.1% TFA in both mobile phases). Concentration of theappropriate fractions afforded7-bromo-N4-(2-(thiophen-2-yl)ethyl)quinoline-2,4-diamine-TFA (39 mg, 41%yield) as a colorless glass. LCMS method: Waters Acquity SDS using thefollowing method: Linear Gradient of 2% to 98% solvent B over 1.00 min;UV visualization at 220 or 254 nm; Column: BEH C18 2.1 mm×50 mm; 1.7 umparticle (Heated to Temp. 50° C.); Flow rate: 0.8 ml/min; Mobile phaseA: 100% Water, 0.05% TFA; Mobile phase B: 100% Acetonitrile, 0.05% TFA.LC RT: 0.75 min. M/Z=350.2.

Step 3. Preparation of7-(1H-pyrazol-3-yl)-N4-(2-(thiophen-2-yl)ethyl)quinoline-2,4-diamine(Compound 351)

A mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(29.4 mg, 0.151 mmol),7-bromo-N4-(2-(thiophen-2-yl)ethyl)quinoline-2,4-diamine, TFA (35 mg,0.076 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (6.18 mg, 7.57 μmol), and cesiumcarbonate (99 mg, 0.303 mmol) in nitrogen-saturated dioxane (757 μL) wasplaced under nitrogen and heated at 95° C. for 2h. The reaction wascooled and stirred at RT. The reaction was quenched with 50% aq. HOAc,diluted to 2 mL with DMF, and purified via preparative LC/MS with thefollowing conditions: Column: XBridge C18, 200 mm×19 mm, 5-μm particles;Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate;Mobile Phase B: 95:5 acetonitrile: ammonium acetate; Gradient: a0-minute hold at 12% B, 12-52% B over 20 minutes, then a 4-minute holdat 100% B; Flow Rate: 20 mL/min; Column Temperature: 25 C. Fractioncollection was triggered by MS signals. Fractions containing the desiredproduct were combined and dried via centrifugal evaporation to afford7-(1H-pyrazol-3-yl)-N4-(2-(thiophen-2-yl)ethyl)quinoline-2,4-diamine(13.6 mg, 54% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 8.03 (d, J=8.9 Hz,1H), 7.83 (br. s, 1H), 7.73-7.78 (m, 1H), 7.63-7.68 (m, 1H), 7.41-7.48(m, 1H), 7.34 (d, J=4.6 Hz, 1H), 6.96-7.00 (m, 3H), 6.84 (d, J=1.8 Hz,1H), 5.80 (s, 1H), 3.47-3.53 (m, 2H), 3.20 (t, J=7.0 Hz, integraldistorted by water suppression). LC RT: 1.36 min. M/Z=336.1.

Compound 323 through Compound 327 were prepared according to thesynthetic procedures described for Compound 321 from the appropriatestarting materials.

Compd. LC/MS RT ¹H NMR No. Structure [M + H]⁺ (min) (500 MHz, DMSO-d₆)323

295.3 0.45 δ 8.29-8.18 (m, 1H), 7.94- 7.93 (m, 1H), 7.92-7.90 (m, 1H),7.83-7.77 (m, 1H), 6.91- 6.84 (m, 1H), 5.98-5.90 (m, 1H), 4.62-4.51 (m,1H), 3.81- 3.70 (m, 2H), 3.66-3.53 (m, 2H), 2.60-2.48 (m, 2H) 324

309.2 0.82 δ 8.25-8.17 (m, 1H), 8.08- 8.00 (m, 1H), 7.93-7.88 (m, 2H),6.89-6.79 (m, 1H), 6.41- 6.29 (m, 1H), 3.77-3.66 (m, 1H), 3.61-3.49 (m,1H), 3.00- 2.87 (m, 1H), 2.17-1.94 (m, 3H), 1.86-1.73 (m, 1H), 1.74-1.58 (m, 2H) 325

295.4 0.55 δ 8.17-8.12 (m, 1H), 7.91- 7.88 (m, 1H), 7.88-7.85 (m, 1H),7.80-7.78 (m, 1H), 6.90- 6.81 (m, 1H), 5.95-5.86 (m, 1H), 4.18-4.08 (m,2H), 3.83- 3.70 (m, 2H), 3.67-3.62 (m, 1H), 3.39-3.35 (m, 2H) 326

323.2 0.65 δ 8.02-7.94 (m, 2H), 7.91- 7.87 (m, 1H), 7.81-7.77 (m, 1H),7.65-7.59 (m, 1H), 7.52- 7.46 (m, 1H), 4.12-3.81 (m, 1H), 3.09-2.66 (m,2H), 2.18- 1.85 (m, 2H), 1.82-1.60 (m, 2H), 1.44-1.20 (m, 4H) 327

309.2 0.45 δ 8.20-8.10 (m, 1H), 7.95- 7.86 (m, 2H), 7.82-7.77 (m, 1H),6.88-6.83 (m, 1H), 5.94- 5.87 (m, 1H), 3.64-3.54 (m, 2H), 3.50-3.42 (m,2H), 3.24- 3.08 (m, 2H), 2.99-2.65 (m, 2H), 1.89-1.76 (m, 1H)

Example III-9: Synthesis of 4-alkoxy Substituted Quinolines by MitsunobuRoute

Step 1. Preparation of 7-bromo-4-(2-(thiophen-3-yl)ethoxy)quinoline

A stirred suspension of 2-(thiophen-3-yl)ethan-1-ol (256 mg, 2.000mmol), triphenylphosphine (367 mg, 1.400 mmol), and 7-bromoquinolin-4-ol(224 mg, 1 mmol) in THF (5000 μl) was heated to reflux then cooled toRT. This suspension was treated with DIAD (272 μl, 1.400 mmol) over 1-2min. The resulting mixture was stirred 1 h at RT then purified by flashchromatography (25-50% EtOAc-hexane). Concentration of the appropriatefractions afforded a pale amber oil. This was treated with ˜5 mL ofhexanes and swirled. A little EtOAc was added, and the mixture wasswirled. A bit of dichloromethane was added, and the mixture was swirledand heated. This gives a solution which was swirled while cooling.Product precipitated onto the glass, and the mixture was then evaporatedto dryness, affording 7-bromo-4-(2-(thiophen-3-yl)ethoxy)quinoline (270mg, 0.81 mmol, 81% yield) as an off-white solid, mp 92-95° C. LCMSmethod: Waters Acquity SDS using the following method: Linear Gradientof 2% to 98% solvent B over 1.00 min; UV visualization at 220 or 254 nm;Column: BEH C18 2.1 mm×50 mm; 1.7 um particle (Heated to Temp. 50° C.);Flow rate: 0.8 ml/min; Mobile phase A: 100% Water, 0.05% TFA; Mobilephase B: 100% Acetonitrile, 0.05% TFA. LC RT: 0.76 min. M/Z=336.1.

Step 2. Preparation of 7-bromo-4-(2-(thiophen-3-yl)ethoxy)quinoline1-oxide

A solution of 7-bromo-4-(2-(thiophen-3-yl)ethoxy)quinoline (250 mg,0.748 mmol) in chloroform (3740 μl) was treated with m-CPBA (516 mg,2.99 mmol). The reaction was stirred 1h at RT then poured intoEtOAc-hexane (to give an organic phase with density <1). A precipitateformed which was re-dissolved by adding more EtOAc and EtOH and heating.This mixture was shaken with 5% aq. sodium thiosulfate.

Saturated aq. sodium bicarbonate was added, and when bubbling ceased themixture was carefully shaken. The org. phase was washed (brine), dried,stripped and chromatographed on silica gel (5-10% MeOH—CH₂Cl₂).Concentration of the appropriate fractions afforded7-bromo-4-(2-(thiophen-3-yl)ethoxy)quinoline 1-oxide (140 mg, 0.40 mmol,53% yield) as an amber glass. LCMS method: Waters Acquity SDS using thefollowing method: Linear Gradient of 2% to 98% solvent B over 1.00 min;UV visualization at 220 or 254 nm; Column: BEH C18 2.1 mm×50 mm; 1.7 umparticle (Heated to Temp. 50° C.); Flow rate: 0.8 ml/min; Mobile phaseA: 100% Water, 0.05% TFA; Mobile phase B: 100% Acetonitrile, 0.05% TFA.LC RT: 0.79 min. M/Z=352.1.

Step 3. Preparation of7-bromo-4-(2-(thiophen-3-yl)ethoxy)quinolin-2-amine

A solution of 7-bromo-4-(2-(thiophen-3-yl)ethoxy)quinoline 1-oxide (137mg, 0.391 mmol) in chloroform (3 mL) was treated with 1 mL of conc. aq.ammonia and stirred rapidly for 3-4 min. Stirring was slowed, and theresulting mixture was treated with Ts-Cl (78 mg, 0.411 mmol) in 1 mL ofchloroform by syringe (sub-surface) over ˜40 seconds. The reaction wasstirred 20 min. at RT then applied to a silica gel column and elutedwith 5-10% MeOH—CH₂Cl₂. Concentration of the appropriate fractionsafforded 7-bromo-4-(2-(thiophen-3-yl)ethoxy)quinolin-2-amine (113 mg,0.324 mmol, 83% yield) as an oil which crystallized upon standing to awaxy tan solid, mp 150-156° C. LCMS method: Waters Acquity SDS using thefollowing method: Linear Gradient of 2% to 98% solvent B over 1.00 min;UV visualization at 220 or 254 nm; Column: BEH C18 2.1 mm×50 mm; 1.7 umparticle (Heated to Temp. 50° C.); Flow rate: 0.8 mi/min; Mobile phaseA: 100% Water, 0.05% TFA; Mobile phase B: 100% Acetonitrile, 0.05% TFA.LC RT: 0.78 min. M/Z=351.1.

Step 4. Preparation of7-(1H-pyrazol-3-yl)-4-(2-(thiophen-3-yl)ethoxy)quinolin-2-amine(Compound 329)

A suspension of5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (16.67 mg,0.086 mmol), 7-bromo-4-(2-(thiophen-3-yl)ethoxy)quinolin-2-amine (15 mg,0.043 mmol), PdCl₂(dppf)-CH₂Cl₂ adduct (7.01 mg, 8.59 μmol), and cesiumcarbonate (42.0 mg, 0.129 mmol) in nitrogen-saturated dioxane (429 μl)was placed under nitrogen and heated at 95° C. for 2h. The reaction wascooled to RT, quenched with a few drops of 50% aq. HOAc, filtered, andpurified via preparative LC/MS with the following conditions: Column:XBridge C18, 200 mm×19 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: a 0-minutehold at 19% B, 19-59% B over 20 minutes, then a 4-minute hold at 100% B;Flow Rate: 20 mL/min; Column Temperature: 25 C. Fraction collection wastriggered by MS and UV signals. Fractions containing the desired productwere combined and dried via centrifugal evaporation to afford7-(1H-pyrazol-3-yl)-4-(2-(thiophen-3-yl)ethoxy)quinolin-2-amine (7.1 mg,48% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 7.82-7.88 (m, 2H), 7.76 (br. s,1H), 7.65 (br. s, 1H), 7.50 (dd, J=4.8, 2.9 Hz, 1H), 7.39 (d, J=2.1 Hz,1H), 7.18 (d, J=4.6 Hz, 1H), 6.80 (d, J=1.8 Hz, 1H), 6.64-6.81 (m, 2H),6.25 (s, 1H), 4.35 (t, J=6.4 Hz, 2H), 3.21 (t, J=6.6 Hz, integraldistorted by water suppression). LC RT: 1.49 min. M/Z=337.1.

Compound 330 and Compound 331 were prepared according to the syntheticprocedures described for Compound 329 from the appropriate startingmaterials.

Compd. LC/MS RT ¹H NMR No. Structure [M + H]⁺ (min) (500 MHz, DMSO-d₆)331

353.1 2.16 δ 7.85 (d, J = 8.3 Hz, 1H), 7.58- 7.63 (m, 2H), 7.47-7.53 (m,2H), 7.38 (d, J = 1.8 Hz, 1H), 7.15-7.20 (m, 2H), 6.74 (s, 2H), 6.25 (s,1H), 4.34 (t, J = 6.4 Hz, 2H), 3.20 (t, J = 6.4 Hz, 2H). 331

353.1 2.12 δ 8.38 (br. s, 3H), 8.07-8.11 (m, 1H), 8.07-8.11 (m, 1H),7.97 (d, J = 8.9 Hz, 1H), 7.81-7.86 (m, 1H), 7.73-7.77 (m, 1H), 7.59-7.63 (m, 1H), 7.50-7.53 (m, 1H), 7.40-7.43 (m, 1H), 7.17- 7.20 (m, 1H),8.44 (t, J = 6.4 Hz, 2H), 3.25 (t, J = 6.4 Hz, integral distorted bywater suppression). Primary amine integrates to three because thissample is a TFA salt.

Example III-10: Synthesis of 4-alkoxy substituted quinolines by Sn_(Ar)on 7-bromo-4-chloroquinolin-2-amine

Step 1. Preparation of(3-(((2-amino-7-bromoquinolin-4-yl)oxy)methyl)oxetan-3-yl)methanol

A stirred solution of oxetane-3,3-diyldimethanol (229 mg, 1.942 mmol) inDMSO (388 μl) was treated with KOtBu (582 μl, 0.582 mmol) in THF over1-2 min. This solution was stirred 5 min. then treated with7-bromo-4-chloroquinolin-2-amine (50 mg, 0.194 mmol). The resultingsolution was heated at 90° C. for 20 min., then the temperature wasraised to 95° C., and stirring was continued for 3h longer. The reactionwas cooled to RT and transferred by pipette into water (with stirring).This gave a suspension with some material adhering to the glass.Stirring was continued for 40 min., after which time the suspension wasfiltered, washed with water, and air-dried to afford(3-(((2-amino-7-bromoquinolin-4-yl)oxy)methyl)oxetan-3-yl)methanol (52mg, 0.153 mmol, 79% yield) as an amorphous tan solid. LCMS method:Waters Acquity SDS using the following method: Linear Gradient of 2% to98% solvent B over 1.00 min; UV visualization at 220 or 254 nm; Column:BEH C18 2.1 mm×50 mm; 1.7 um particle (Heated to Temp. 50 20° C.); Flowrate: 0.8 ml/min; Mobile phase A: 100% Water, 0.05% TFA; Mobile phase B:100% Acetonitrile, 0.05% TFA. LC RT: 0.57 min. M/Z=341.1.

Step 2. Preparation of(3-(((2-amino-7-(thiophen-3-yl)quinolin-4-yl)oxy)methyl)oxetan-3-yl)methanol(Compound 332)

A suspension of(3-(((2-amino-7-bromoquinolin-4-yl)oxy)methyl)oxetan-3-yl)methanol (20mg, 0.059 mmol), thiophen-3-ylboronic acid (15.09 mg, 0.118 mmol),PdCl₂(dppf)-CH₂Cl₂ adduct (4.82 mg, 5.90 μmol), and cesium carbonate(57.6 mg, 0.177 mmol) in nitrogen-saturated dioxane (590 μl) was placedunder nitrogen and heated to 95° C. After 2h, LCMS shows a completereaction. It was cooled and quenched with a few drops of 50% aq. HOAc.When all the solids had dissolved, the reaction was diluted to 2 mL withDMF and filtered. The crude material was purified via preparative LC/MSwith the following conditions: Column: XBridge C18, 200 mm×19 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammoniumacetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammoniumacetate; Gradient: a 0-minute hold at 14% B, 14-54% B over 20 minutes,then a 4-minute hold at 100% B; Flow Rate: 20 mL/min; ColumnTemperature: 25 C. Fraction collection was triggered by MS and UVsignals. Fractions containing the desired product were combined anddried via centrifugal evaporation to afford(3-(((2-amino-7-(thiophen-3-yl)quinolin-4-yl)oxy)methyl)oxetan-3-yl)methanol(11.6 mg, 55% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 7.95-7.97 (m, 1H),7.84 (d, J=8.6 Hz, 1H), 7.70 (d, J=1.8 Hz, 1H), 7.65-7.68 (m, 1H),7.61-7.64 (m, 1H), 7.50 (dd, J=8.6, 1.5 Hz, 1H), 6.34 (s, 2H), 6.25 (s,1H), 4.55 (d, J=6.1 Hz, 2H), 4.48 (d, J=6.1 Hz, 2H), 4.28 (s, 2H), 3.82(s, 2H). LC RT: 1.33 min. M/Z=343.3.

Compound 333 was prepared according to the synthetic proceduresdescribed for Compound 332 from the appropriate starting materials.

¹H NMR (500 MHz, DMSO-d₆) δ 7.84 (d, J=8.3 Hz, 1H), 7.81 (s, 1H), 7.74(d, J=1.3 Hz, 1H), 7.59 (dd, J=8.3, 1.0 Hz, 1H), 6.78 (s, 1H), 6.33 (s,2H), 6.26 (s, 1H), 4.55 (d, J=5.6 Hz, 1H), 4.49 (d, J=5.1 Hz, 1H), 4.28(s, 2H), 3.82 (s, 2H). LC RT: 0.93 min. M/Z=326.9.

Example III-11: Synthesis of 4-alkoxy Substituted Quinolines by Sn_(Ar)on 7-bromo-4-chloroquinolin-2-amine

Step 1. Preparation of(1-(((2-amino-7-bromoquinolin-4-yl)oxy)methyl)cyclobutyl)methanol

(1-(((2-amino-7-bromoquinolin-4-yl)oxy)methyl)cyclobutyl)methanol wasprepared from cyclobutane-1,1-diyldimethanol and7-bromo-4-chloroquinolin-2-amine in 89% yield using the procedure forthe preparation of(3-(((2-amino-7-bromoquinolin-4-yl)oxy)methyl)oxetan-3-yl)methanol. LCMSmethod: Waters Acquity SDS using the following method: Linear Gradientof 2% to 98% solvent B over 1.00 min; UV visualization at 220 or 254 nm;Column: BEH C18 2.1 mm×50 mm; 1.7 um particle (Heated to Temp. 50° C.);Flow rate: 0.8 ml/min; Mobile phase A: 100% Water, 0.05% TFA; Mobilephase B: 100% Acetonitrile, 0.05% TFA.LC RT: 0.82 min. M/Z=339.2.

Step 2. Preparation of(1-(((2-amino-7-(thiophen-2-yl)quinolin-4-yl)oxy)methyl)cyclobutyl)methanol(Compound 334)

A suspension of4,4,5,5-tetramethyl-2-(thiophen-2-yl)-1,3,2-dioxaborolane (24.92 mg,0.119 mmol),(1-(((2-amino-7-bromoquinolin-4-yl)oxy)methyl)cyclobutyl)methanol (20mg, 0.059 mmol), cesium carbonate (58.0 mg, 0.178 mmol), andPdCl₂(dppf)-CH₂Cl₂ adduct (4.84 mg, 5.93 μmol) in nitrogen-saturateddioxane (593 μl) was placed under nitrogen and heated at 95° C. for 1.5h. The reaction was then cooled to room temperature, quenched with 50%aq. HOAc, filtered, and filtered. The crude material was purified viapreparative LC/MS with the following conditions: Column: XBridge C18,200 mm×19 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:waterwith 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:waterwith 10-mM ammonium acetate; Gradient: a 0-minute hold at 20% B, 20-60%B over 20 minutes, then a 4-minute hold at 100% B; Flow Rate: 20 mL/min;Column Temperature: 25° C. Fraction collection was triggered by MS andUV signals. Fractions containing the desired product were combined anddried via centrifugal evaporation to afford(1-(((2-amino-7-(thiophen-2-yl)quinolin-4-yl)oxy)methyl)cyclobutyl)methanol(11.2 mg, 56% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 7.84 (d, J=8.4 Hz,1H), 7.61 (d, J=1.6 Hz, 1H), 7.56-7.60 (m, 2H), 7.47 (dd, J=8.4, 1.8 Hz,1H), 7.17 (dd, J=4.7, 3.9 Hz, 1H), 6.40 (s, 2H), 6.24 (s, 1H), 4.06 (s,2H), 1.87-2.00 (n, 6H). One methylene is not visible, likely due tooverlap with the suppressed water peak. LC RT: 1.79 min. M/Z=341.2.

Compound 335 through Compound 337 were prepared according to thesynthetic procedures described for Compound 334 from the appropriatestarting materials.

Compd. LC/MS RT ¹H NMR No. Structure [M + H]⁺ (min) (500 MHz, DMSO-d₆)335

325.2 1.21 δ 7.84 (d, J = 8.4 Hz, 1H), 7.81 (s, 1H), 7.74 (d, J = 0.7Hz, 1H), 7.59 (dd, J = 8.5, 0.6 Hz, 1H), 6.78 (d, J = 2.0 Hz, 1H), 6.35(s, 2H), 6.23 (s, 1H), 4.06 (s, 2H), 1.89-2.00 (m, 6H). One methylenegroup is not visible, likely due to water suppression. 336

341.2 1.79 δ 7.94-7.97 (m, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.70 (br. s,1H), 7.65-7.68 (m, 1H), 7.61-7.64 (m, 1H), 7.53 (dd, J = 8.5, 1.5 Hz,1H), 6.42 (br. s, 2H), 6.24 (s, 1H), 4.06 (s, 2H), 1.90-1.98 (m, 6H).One methylene group is not visible, likely due to water suppression. 337

352.9 1.95 δ 8.04 (br s, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.78 (br. s,1H), 7.67- 7.73 (m, 2H), 7.61-7.64 (m, 1H), 7.46 (br. s, 2H), 6.29 (s,1H), 4.28 (t, J = 4.6 Hz, 2H), 2.08-2.16 (m, 2H). Two protons fromsidechain are not visible, likely due to overlap with DMSO-d6 peak.

Example III-12: Synthesis of 4-amino Substituted Quinolines UsingN-(7-bromo-4-chloroquinolin-2-yl)benzamide

Step 1. Preparation ofN-(4-chloro-7-(thiophen-3-yl)quinolin-2-yl)benzamide

A reaction vial was charged withN-(7-bromo-4-chloroquinolin-2-yl)benzamide (164 mg, 0.454 mmol),thiophen-3-ylboronic acid (75 mg, 0.590 mmol), and potassium phosphate(337 mg, 1.587 mmol). Dioxane (6.25 mL) and water (0.25 mL) were thenadded. The reaction was degassed for 10 minutes with a stream ofnitrogen. Tetrakis(triphenylphosphine)palladium(0) (52.4 mg, 0.045 mmol)was then added and the vial was sealed and warmed to 90° C. After threehours, the cooled reaction was partitioned between water and ethylacetate. The water layer was extracted with an additional portion ofethyl acetate. The combined organic layers were then washed with brine.Drying over magnesium sulfate, filtration and evaporation provided thecrude product. The product was purified on a 24 g silica gel column,eluting with 20-100% ethyl acetate in hexanes. Evaporation of theproduct containing fractions providedN-(4-chloro-7-(thiophen-3-yl)quinolin-2-yl)benzamide (158 mg, 0.433mmol, 95% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 11.35 (br s, 1H), 8.53 (s,1H), 8.20 (m, 1H), 8.17 (s, 2H), 8.12-8.05 (m, 3H), 7.79-7.71 (m, 2H),7.64 (t, J=7.2 Hz, 1H), 7.55 (t, J=7.8 Hz, 2H).

Step 2. Preparation of(3-(((2-amino-7-(thiophen-3-yl)quinolin-4-yl)amino)methyl)oxetan-3-yl)methanol(Compound 338)

A reaction vial was charged withN-(4-chloro-7-(thiophen-3-yl)quinolin-2-yl)benzamide (21.2 mg, 0.058mmol) in dimethylsulfoxide (0.75 mL).(3-(Aminomethyl)oxetan-3-yl)methanol hydrochloride (44.6 mg, 0.291 mmol)and diisopropylethylamine (60.9 μl, 0.349 mmol) were added and the vialwas flushed with nitrogen. The reaction was then warmed to 120° C. andstirred overnight. The cooled reaction was diluted with DMSO (1 mL) andpurified by preparative LC using the following conditions: Column:XBridge C18, 200 mm×19 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: a 0-minutehold at 10% B, 10-50% B over 20 minutes, then a 4-minute hold at 100% B;Flow Rate: 20 mL/min; Column Temperature: 25° C. Fraction collection wastriggered by MS signals. Fractions containing the desired product werecombined and dried via centrifugal evaporation to give(3-(((2-amino-7-(thiophen-3-yl)quinolin-4-yl)amino)methyl)oxetan-3-yl)methanol(7.0 mg, 0.021 mmol, 35%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.01 (br s, 1H),7.87 (d, J=8.9 Hz, 1H), 7.71 (s, H), 7.71-7.68 (m, 1H), 7.60 (d, J=4.9Hz, 1H), 7.57 (br d, J=8.9 Hz, 1H), 6.91 (br s, 2H), 5.49 (s, 1H), 4.11(br s, 4H), 3.59 (s, 4H). LC/MS conditions: Column: Waters XBridge C18,2.1 mm×50 mm, 1.7 μm particles; Mobile Phase A: 5:95 acetonitrile:waterwith 0.1% trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:waterwith 0.1% trifluoroacetic acid; Temperature: 50° C.; Gradient: 0% B to100% B over 3 min, then a 0.50 min hold at 100% B; Flow: 1 mL/min;Detection: MS and UV (220 nm). LC RT: 1.13 min. M/Z=341.92.

Example III-13: Synthesis of 4-heteroaryl Substituted Quinolines

Step 1. Preparation of4,7-bis(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)quinolin-2-amine

To a solution of 7-bromo-4-chloroquinolin-2-amine (431.2 mg, 1.67 mmol)in anhydrous dioxane (5 ml) and anhydrous DMF (5 ml), at roomtemperature under nitrogen atmosphere, was added K₃PO₄ (2M aq. solution,2.51 ml, 5.02 mmol) followed by1-(tetrahydro-2h-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1h-pyrazole(605 mg, 2.18 mmol). The mixture was sparged with argon forapproximately thirty minutes before PdCl₂(dppf)-CH₂Cl₂ (68.4 mg, 0.084mmol) was added and the mixture was heated, with stirring, at 90° C.After 12 hours, the reaction was allowed to cool to room temperaturebefore being partitioned between DCM and water. The layers wereseparated and the aqueous layer was extracted twice more with DCM. Theseorganic extracts were combined with the original organic layer and werewashed with brine, dried over anhydrous sodium sulfate, filtered througha pad of Celite then concentrated in vacuo to afford a dark brown oil.The crude product was purified by silica gel chromatography (IscoCombiFlash; RediSep normal phase silica flash column (40 g); EtOAc inhexane; 0-100% gradient) to afford the title compound as an oil (87.5mg; 11.8% yield). ¹H NMR (400 MHz, DMSO-d₆) δ 7.75-7.72 (m, 1H), 7.69(d, J=1.4 Hz, 1H), 7.60 (d, J=1.6 Hz, 1H), 7.47 (dd, J=8.4, 1.7 Hz, 1H),7.28 (dd, J=8.5, 1.3 Hz, 1H), 6.88-6.83 (m, 1H), 6.77 (s, 2H), 6.57-6.51(m, 2H), 5.34-5.27 (m, 1H), 5.07 (br dd, J=7.0, 2.2 Hz, 1H), 3.92-3.83(m, 1H), 3.63-3.53 (m, 1H), 2.49-2.27 (m, 4H), 1.92 (br d, J=12.4 Hz,2H), 1.79 (br d, J=12.7 Hz, 2H), 1.62-1.42 (m, 6H). LC/MS Conditions:Linear Gradient of 2% to 98% solvent B over 1.7 min; UV visualization at220 nm; Column: BEH C18 2.1 mm×50 mm; 1.7 um particle (Heated to Temp.50° C.); Flow rate: 0.8 ml/min; Mobile phase A: 100% Water, 0.05% TFA;Mobile phase B: 100% Acetonitrile, 0.05% TFA. MS (ES): m/z=445 [M+H]⁺.T_(r)=0.71 min.

Step 2. Preparation of 4,7-di(1H-pyrazol-5-yl)quinolin-2-amine, HCl(Compound 339)

To a solution of4,7-bis(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)quinolin-2-amine(87.5 mg, 0.197 mmol) in MeOH (1 ml), at room temperature in a sealablereaction vial, was added HCl (4N in dioxane; 0.3 ml, 1.20 mmol). Thevial was capped and the resulting solution was stirred for twentyminutes before being concentrated in vacuo to afford a tan solid. Thecrude material was dissolved in MeOH, filtered through an Acrodisc 13 mm0.45 μm syringe filter then purified by RP Prep HPLC with the followingconditions: Column: Phen Axia C18 30×100, 5 μm particle size; MobilePhase A:=90:10 H2O:MeOH with 0.1% trifluoroacetic acid; Mobile PhaseB:=10:90 H₂O:MeOH with 0.1% trifluoroacetic acid; Run time=20 minutesusing 10 minute gradient from 20 to 100% Mobile Phase B; Flow rate=40mL/minute. Fractions containing desired product, as determined by LCMS,were combined and concentrated in vacuo to remove volatiles. Theresultant residue was treated with HCl (4N in dioxane; 0.3 ml, 1.20mmol) and stirred at ambient temperature for ten minutes before beingconcentrated in vacuo to afford the title compound as a pale yellowsolid (38.4 mg; 61.8% yield) as the HCl salt. ¹H NMR (DMSO-d₆): δ8.84-8.62 (m, 2H), 8.16 (d, J=1.4 Hz, 1H), 8.04 (d, J=2.3 Hz, 1H), 7.97(dd, J=8.7, 1.6 Hz, 1H), 7.88 (d, J=2.2 Hz, 1H), 7.30 (s, 1H), 6.91-6.85(m, 2H), 6.00-5.11 (m, 3H). Waters Acquity SDS using the followingmethod: Linear Gradient of 2% to 98% solvent B over 1.7 min; UVvisualization at 220 nm; Column: BEH C18 2.1 mm×50 mm; 1.7 um particle(Heated to Temp. 50° C.); Flow rate: 0.8 ml/min; Mobile phase A: 100%Water, 0.05% TFA; Mobile phase B: 100% Acetonitrile, 0.05% TFA.T_(r)=0.55 min. MS (ES): m/z=277 [M+H]⁺.

Example III-14: Synthesis of 4-aminoethyl Substituted Quinolines

Step 1. Preparation of7-bromo-N4-(2-(pyridazin-3-yl)ethyl)quinolin-2,4-diamine

To a homogeneous mixture of 7-bromo-4-chloroquinolin-2-amine (150 mg,0.58 mmol) in NMP (2 mL), in a sealable reaction vial, was added2-pyridazin-3-ylethanamine (100 mg, 0.81 mmol) followed by DIPEA (0.42mL, 2.40 mmol). The vial was capped and the mixture was stirred andheated at 120° C. for 15 hours. After cooling to room temperature, thereaction mixture was purified directly by silica gel chromatography(Isco CombiFlash; RediSep normal phase silica flash column (24 g); MeOHin DCM; 0-20% gradient) to afford the title compound as a yellow residue(101.4 mg; 45.5% yield).

LC/MS conditions: Linear Gradient of 2% to 98% solvent B over 1.7 min;UV visualization at 220 nm; Column: BEH C18 2.1 mm×50 mm; 1.7 umparticle (Heated to Temp. 50° C.); Flow rate: 0.8 mi/min; Mobile phaseA: 100% Water, 0.05% TFA; Mobile phase B: 100% Acetonitrile, 0.05% TFA.T_(r)=0.62 min. MS (ES): m/z=344 [M+H]⁺.

Step 2. Preparation of7-(1H-pyrazol-3-yl)-N4-(2-(pyridazin-3-yl)ethyl)quinolin-2,4-diamine(Compound 340)

A mixture of 7-bromo-N4-(2-(pyridazin-3-yl)ethyl)quinoline-2,4-diamine(20 mg, 0.06 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane)-pyrazole(24.80 mg, 0.13 mmol) and Cs₂CO₃ (56.8 mg, 0.17 mmol) in dioxane (1.5mL) and water (0.2 mL), in a sealable reaction vial, was sparged withargon for approximately ten minutes before PdCl₂(dppf)-CH₂Cl₂ adduct(9.49 mg, 0.012 mmol) was added. The vial was sealed and the reactionwas heated at 90° C. for 18 hours. After cooling to room temperature,the reaction was concentrated in vacuo to remove volatiles, dissolved inDMF then purified by preparative HPLC/MS via the following conditions:Column: XBridge C18, 200 mm×19 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: a 0-minutehold at 0% B, 0-40% B over 20 minutes, then a 4-minute hold at 100% B;Flow Rate: 20 mL/min; Column Temperature: 25° C. Fraction collection wastriggered by MS signals. Fractions containing the desired product werecombined and dried via centrifugal evaporation to afford the titlecompound (9.7 mg; 47.5% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 9.11 (br d,J=3.1 Hz, 1H), 8.24-8.17 (m, 1H), 8.14 (br d, J=8.5 Hz, 1H), 7.97-7.88(m, 1H), 7.87-7.79 (m, 2H), 7.70-7.57 (m, 3H), 6.85 (d, J=1.2 Hz, 1H),5.90 (s, 1H), 3.81-3.72 (m, integral distorted by water suppression),3.33 (br t, J=7.2 Hz, integral distorted by water suppression). LC/MSconditions: Column: Waters XBridge C18, 2.1 mm×50 mm, 1.7 μm particles;Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate;Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate;Temperature: 50° C.; Gradient: 0% B to 100% B over 3 min, then a 0.50min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). LCRT: 0.76 min. M/Z=332.12.

Compound 341:N4-(2-(pyridazin-3-yl)ethyl)-7-(thiophen-3-yl)quinolin-2,4-diamine

Compound 341 (8.8 mg; 41.7% yield) was prepared following a procedureanalogous to that for the synthesis of Compound 340, except that4,4,5,5-tetramethyl-2-(thiophen-3-yl)-1,3,2-dioxaborolane (26.9 mg; 0.13mmol) was used instead of3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane)-pyrazole. ¹H NMR (500 MHz,DMSO-d₆) δ 9.17-9.04 (m, 1H), 8.25-8.18 (m, 1H), 8.17-8.11 (m, 1H),8.09-8.03 (m, 1H), 7.79-7.70 (m, 3H), 7.68-7.59 (m, 4H), 5.90 (s, 1H),3.77 (q, J=6.5 Hz, integral distorted by water suppression), 3.33 (t,J=7.2 Hz, integral distorted by water suppression). LC RT: 1.27 min.M/Z=348.08.

Compound 342:N4-(2-(pyridazin-3-yl)ethyl)-7-(thiophen-2-yl)quinolin-2,4-diamine

Compound 342 (8.6 mg; 40.8% yield) was prepared following a procedureanalogous to that for the synthesis of Compound 340), except that4,4,5,5-tetramethyl-2-(thiophen-2-yl)-1,3,2-dioxaborolane (26.9 mg; 0.13mmol) was used instead of3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane)-pyrazole. ¹H NMR (500 MHz,DMSO-d₆) δ 9.19-8.98 (m, 1H), 8.19 (br t, J=5.2 Hz, 1H), 8.10 (d, J=8.5Hz, 1H), 7.73-7.57 (m, 6H), 7.24-7.17 (m, 1H), 5.87 (s, 1H), 3.76-3.72(m, integral distorted by water suppression), 3.31 (t, J=7.2 Hz,integral distorted by water suppression). LC RT: 1.23 min. M/Z=348.10.

Example III-15: Preparation of7-(1H-pyrazol-1-yl)-N4-(2-(pyridazin-3-yl)ethyl)quinoline-2,4-diamine(Compound 343)

To a mixture of7-bromo-N4-(2-(pyridazin-3-yl)ethyl)quinoline-2,4-diamine (20 mg, 0.06mmol) in anhydrous DMSO (2.9 mL), in a sealable reaction vial, was added1H-pyrazole (7.91 mg, 0.12 mmol) and copper(I) iodide (22.13 mg, 0.12mmol) followed by Na₂CO₃ (24.63 mg, 0.23 mmol). The homogeneous mixturewas sparged with argon for approximately 5 minutes beforeN,N′-dimethylethylenediamine (0.02 mL, 0.19 mmol) was added. The vialwas capped and the reaction heated at 120° C. with stirring. After 18hours, the reaction was cooled to room temperature, diluted with DMSO,then purified via preparative LC/MS with the following conditions:Column: XBridge C18, 200 mm×19 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: a 0-minutehold at 5% B, 5-45% B over 20 minutes, then a 4-minute hold at 100% B;Flow Rate: 20 mL/min; Column Temperature: 25° C. Fraction collection wastriggered by MS signals. Fractions containing the desired product werecombined and dried via centrifugal evaporation to afford the titlecompound (7.5 mg; 37.2% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 9.08 (br d,J=3.1 Hz, 1H), 8.51 (d, J=2.1 Hz, 1H), 8.01 (d, J=9.2 Hz, 1H), 7.80-7.71(m, 2H), 7.68-7.60 (m, 2H), 7.41-7.23 (m, 1H), 6.74-6.50 (m, 2H), 5.84(s, 1H), 3.77-3.59 (m, integral distorted by water suppression), 3.30(br t, J=7.0 Hz, 2H). LC/MS Conditions: Column: Waters XBridge C18, 2.1mm×50 mm, 1.7 μm particles; Mobile Phase A: 5:95 acetonitrile:water with10 mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10mM ammonium acetate; Temperature: 50° C.; Gradient: 0% B to 100% B over3 min, then a 0.50 min hold at 100% B; Flow: 1 mL/min; Detection: MS andUV (220 nm). LC RT: 0.83 min. M/Z=332.12.

Example III-16:7-(1H-pyrazol-3-yl)-N4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)quinoline-2,4-diamine(Compound 344)

Step 1. Preparation of7-bromo-N4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)quinoline-2,4-diamine

To a homogeneous mixture of 7-bromo-4-chloroquinolin-2-amine (100 mg,0.39 mmol) in NMP (0.5 mL), in a sealable reaction vial, was added4-(2-aminoethyl)tetrahydropyran hydrochloride (90 mg, 0.54 mmol)followed by DIPEA (0.35 mL, 2.00 mmol). The vial was capped and themixture was stirred and heated at 120° C. for 20 hours. After cooling toroom temperature, the reaction was partitioned between EtOAc and brine.The layers were separated and the aqueous layer was extracted once morewith EtOAc. The organic layers were combined, dried (Na₂SO₄), filteredand concentrated in vacuo to afford a gold oil which was purifieddirectly by silica gel chromatography (Isco CombiFlash; RediSep normalphase silica flash column (12 g); MeOH in DCM; 0-20% gradient) to affordthe title compound as an off-white solid (93.0 mg; 68.4% yield). ¹H NMR(400 MHz, DMSO-d₆) δ 8.20-8.09 (m, 1H), 7.93 (br s, 1H), 7.69 (d, J=2.0Hz, 1H), 7.55-7.24 (m, 3H), 5.80 (s, 1H), 3.85 (dd, J=11.1, 3.5 Hz, 2H),3.30-3.25 (m, 4H), 1.62 (br t, J=11.8 Hz, 5H), 1.33-1.13 (m, 2H). LC/MSConditions: Linear Gradient of 2% to 98% solvent B over 1.7 min; UVvisualization at 220 nm; Column: BEH C18 2.1 mm×50 mm; 1.7 um particle(Heated to Temp. 50° C.); Flow rate: 0.8 ml/min; Mobile phase A: 100%Water, 0.05% TFA; Mobile phase B: 100% Acetonitrile, 0.05% TFA.T_(r)=0.70 min. MS (ES): m/z=350 [M+H]⁺.

Step 2. Preparation of7-(1H-pyrazol-3-yl)-N4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)quinoline-2,4-diaminediamine (Compound 344)

A mixture of7-bromo-N4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)quinoline-2,4-diamine (18mg, 0.05 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane)-pyrazole(21.9 mg, 0.11 mmol) and Cs₂CO₃ (50.2 mg, 0.15 mmol) in dioxane (1.5 mL)and water (0.2 mL), in a sealable reaction vial, was sparged with argonfor approximately ten minutes before PdCl₂(dppf)-CH₂Cl₂ adduct (8.39 mg,0.010 mmol) was added. The vial was sealed and the reaction was heatedat 90° C. for 17 hours. After cooling to room temperature, the reactionwas concentrated in vacuo to remove volatiles, dissolved in DMF thenpurified by preparative HPLC/MS via the following conditions: Column:XBridge C18, 200 mm×19 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 0.1% trifluoroacetic acid; Mobile Phase B: 95:5acetonitrile:water with 0.1% trifluoroacetic acid; Gradient: a 0-minutehold at 0% B, 0-40% B over 20 minutes, then a 4-minute hold at 100% B;Flow Rate: 20 mL/min; Column Temperature: 25° C. Fraction collection wastriggered by MS and UV signals. Fractions containing the desired productwere combined and dried via centrifugal evaporation to afford the titlecompound (17.2 mg; 97% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 8.22 (br d,J=8.5 Hz, 1H), 8.12-8.03 (m, 1H), 7.97-7.90 (m, 1H), 7.90-7.80 (m, 2H),7.59 (br s, 2H), 6.85 (s, 1H), 5.79 (s, 1H), 3.85 (br dd, J=11.3, 3.1Hz, 2H), 3.44-3.24 (m, integral distorted by water suppression),1.70-1.43 (m, 6H), 1.31-1.18 (m, 2H). Some protons are unobserved eitherdue to overlap with suppressed water peak or low integration. LC/MSconditions: Column: Waters XBridge C18, 2.1 mm×50 mm, 1.7 μm particles;Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate;Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate;Temperature: 50° C.; Gradient: 0% B to 100% B over 3 min, then a 0.50min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). LCRT: 1.12 min. M/Z=338.26.

Compound 345:N4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-7-(thiophen-3-yl)quinoline-2,4-diamine

Compound 345 (15.3 mg; 84% yield) was prepared following a procedureanalogous to that for the synthesis of Compound 344, except that4,4,5,5-tetramethyl-2-(thiophen-3-yl)-1,3,2-dioxaborolane (23.8 mg; 0.11mmol) was used instead of3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane)-pyrazole. ¹H NMR (500 MHz,DMSO-d₆) δ 8.26-8.19 (m, 1H), 8.14-8.05 (m, 2H), 7.81-7.77 (m, 1H),7.76-7.71 (m, 2H), 7.65-7.52 (m, 3H), 5.80 (s, 1H), 3.85 (br dd, J=11.3,3.4 Hz, 2H), 3.45-3.25 (m, integral distorted by water suppression),1.68-1.58 (m, 5H), 1.30-1.18 (m, 2H). Protons may be unobserved eitherdue to overlap with suppressed water peak or low integration. LC RT:1.62 min. M/Z=354.06.

Example III-17:7-(1H-pyrazol-1-yl)-N4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)quinoline-2,4-diamine(Compound 346)

To a mixture of7-bromo-N4-(2-(tetrahydro-2H-pyran-4-yl)ethyl)quinoline-2,4-diamine(17.5 mg, 0.05 mmol) in anhydrous DMSO (2.5 mL), in a sealable reactionvial, was added 1H-pyrazole (6.80 mg, 0.10 mmol) and copper(I) iodide(19.03 mg, 0.10 mmol) followed by Na₂CO₃ (21.18 mg, 0.20 mmol). Thehomogeneous mixture was sparged with Argon for approximately 5 minutesbefore N,N′-dimethylethylenediamine (0.02 mL, 0.19 mmol) was added. Thevial was capped and the reaction heated at 120° C. with stirring. After18 hours, the reaction was cooled to room temperature, diluted withDMSO, then purified via preparative LC/MS with the following conditions:Column: XBridge C18, 200 mm×19 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: a 0-minutehold at 6% B, 6-46% B over 28 minutes, then a 4-minute hold at 100% B;Flow Rate: 20 mL/min; Column Temperature: 25 C. Fraction collection wastriggered by MS signals. Fractions containing the desired product werecombined and dried via centrifugal evaporation to afford the titlecompound (13.3 mg; 76% yield). ¹H NMR (500 MHz, DMSO-d₆) δ 8.56 (br s,1H), 8.18-8.03 (m, 1H), 7.83-7.70 (m, 2H), 7.60 (br dd, J=8.6, 2.0 Hz,1H), 7.16-6.94 (m, 1H), 6.76-6.51 (m, 3H), 5.87-5.63 (m, 1H), 3.87-3.78(m, 1H), 3.69-3.58 (m, 3H), 3.37-3.17 (m, 2H), 1.69-1.56 (m, 5H),1.28-1.14 (m, 2H). Analytical LC/MS was used to determine the finalpurity. Injection 1 conditions: Column: Waters XBridge C18, 2.1 mm×50mm, 1.7 μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mMammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10 mMammonium acetate; Temperature: 50° C.; Gradient: 0% B to 100% B over 3min, then a 0.50 min hold at 100% B; Flow: 1 mL/min; Detection: MS andUV (220 nm). LC RT: 1.24 min. M/Z=337.91.

Example III-18: 4-(1H-pyrazol-4-yl)-7-(1H-pyrazol-5-yl)quinolin-2-amine(Compound 347)

Step 1. Preparation of4-(1H-pyrazol-4-yl)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)quinolin-2-amine

To a mixture of4-chloro-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)quinolin-2-amine(48.3 mg, 0.15 mmol) and 1-Boc-pyrazole-4-boronic acid pinacol ester(43.2 mg, 0.15 mmol) in anhydrous dioxane (3 mL), in a sealable reactionvial, was added potassium phosphate (2M aqueous; 0.22 mL; 0.44 mmol).The resulting mixture was sparged with argon for approximately 10 minbefore Xphos Pd G2 (CAS: 1310584-14-5; 5.78 mg, 7.34 μmol) was added.The mixture was sparged with argon for approximately 2 minutes beforethe vial was sealed and the mixture stirred at 65° C. After 14 hours,the reaction was cooled to room temperature then purified by silica gelchromatography (Isco CombiFlash; RediSep normal phase silica flashcolumn (12 g); MeOH in DCM; 0-20% gradient) to afford the title compoundas a yellow residue (31.0 mg; 58.6% yield). Waters Acquity SDS using thefollowing method: Linear Gradient of 2% to 98% solvent B over 1.7 min;UV visualization at 220 nm; Column: BEH C18 2.1 mm×50 mm; 1.7 umparticle (Heated to Temp. 50° C.); Flow rate: 0.8 ml/min; Mobile phaseA: 100% Water, 0.05% TFA; Mobile phase B: 100% Acetonitrile, 0.05% TFA.T_(r)=0.66 min. MS (ES): m/z=361 [M+H]⁺.

Step 2. Preparation of4-(1H-pyrazol-4-yl)-7-(1H-pyrazol-5-yl)quinolin-2-amine (Compound 347)

To a solution of4-(1H-pyrazol-4-yl)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)quinolin-2-amine(31.0 mg, 0.09 mmol) in anyhydrous MeOH (1 mL), at room temperatureunder nitrogen, was added p-toluenesulfonic acid (4.2 mg, 0.024 mmol).The resulting mixture was stirred at ambient temperature for one hourthen concentrated in vacuo to remove volatiles. The crude material wasdissolved in DMF, filtered through an Acrodisc 13 mm 0.45 μm syringefilter then purified by RP Prep HPLC with the following conditions:Column: XBridge C18, 200 mm×19 mm, 5-μm particles; Mobile Phase A: 5:95acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5acetonitrile:water with 10-mM ammonium acetate; Gradient: a 0-minutehold at 2% B, 2-42% B over 20 minutes, then a 4-minute hold at 100% B;Flow Rate: 20 mL/min; Column Temperature: 25 C. Fraction collection wastriggered by MS signals. Fractions containing the desired product werecombined and dried via centrifugal evaporation to afford the titlecompound (1.7 mg; 6.8%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.11-7.94 (m, 2H),7.92-7.84 (m, 2H), 7.78-7.70 (m, 1H), 7.68-7.58 (m, 1H), 6.79 (d, J=1.4Hz, 1H), 6.72 (s, 1H), 6.38 (br s, 2H). Protons may be unobserved eitherdue to overlap with suppressed water peak or low integration. LC/MSconditions: Column: Waters XBridge C18, 2.1 mm×50 mm, 1.7 μm particles;Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate;Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate;Temperature: 50° C.; Gradient: 0% B to 100% B over 3 min, then a 0.50min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). LCRT: 0.71 min. M/Z=277.04.

Compound 348:2-(4-(2-amino-7-(1H-pyrazol-5-yl)quinolin-4-yl)-1H-pyrazol-1-yl)ethan-1-ol

Compound 348) (1.3 mg; 3.3% yield) was prepared following a procedureanalogous to that for the synthesis of Compound 347, except that2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1h-pyrazol-1-yl)ethanol(35.0 mg, 0.15 mmol) was used instead of 1-Boc-pyrazole-4-boronic acidpinacol ester. ¹H NMR (500 MHz, DMSO-d₆) δ 8.29-8.16 (m, 1H), 8.04-7.92(m, 2H), 7.90-7.83 (m, 1H), 7.82-7.55 (m, 2H), 6.88-6.68 (m, 2H), 4.27(t, J=5.3 Hz, 2H), 3.88-3.74 (m, 2H). Protons may be unobserved eitherdue to overlap with suppressed water peak or low integration. LC RT:0.80 min. M/Z=321.07.

Example III-19: Preparation of(R)-1-((2-amino-7-(1H-pyrazol-5-yl)quinolin-4-yl)oxy)-3-morpholinopropan-2-ol(Compound 349)

Step 1: Preparation of7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)quinolin-4-ol

7-Bromoquinolin-4-ol (1.5 g, 6.69 mmol) and1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(2.421 g, 8.70 mmol) were suspended in a 1:1 mixture of Dioxane:DMF (33mL). Nitrogen gas was bubbled through the reaction mixture for 5 min,then PdCl₂(dppf)-CH₂Cl₂ adduct (0.273 g, 0.335 mmol) was added followedby aqueous tripotassium phosphate (2M, 10.04 mL, 20.08 mmol). Nitrogengas was bubbled through the reaction mixture for another 5 minutes. Thereaction was then heated under N₂ for 16 h. After cooling to rt, thereaction mixture was partitioned between EtOAc and H₂O. The organiclayer was separated and the aqueous phase was extracted with 2additional portions of EtOAc. The combined organic phases were driedover Na₂SO₄, filtered through celite and concentrated. The residue wastriturated with Et₂O to afford7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)quinolin-4-ol as a lightbrown solid (1.20 g). ¹H NMR (400 MHz, DMSO-d₆) δ 11.90 (br d, J=5.0 Hz,1H), 8.18 (d, J=8.4 Hz, 1H), 7.96 (dd, J=7.2, 6.0 Hz, 1H), 7.69 (d,J=1.2 Hz, 1H), 7.63 (d, J=1.6 Hz, 1H), 7.45 (dd, J=8.4, 1.5 Hz, 1H),6.58 (d, J=1.8 Hz, 1H), 6.08 (d, J=7.3 Hz, 1H), 5.28 (dd, J=9.9, 2.0 Hz,1H), 4.02 (br d, J=12.5 Hz, 1H), 3.62 (td, J=10.9, 3.3 Hz, 1H),2.46-2.33 (m, 1H), 1.95 (br d, J=8.6 Hz, 1H), 1.80 (br d, J=13.0 Hz,1H), 1.66-1.46 (m, 3H).

Step 2. Preparation of4-(((R)-oxiran-2-yl)methoxy)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)quinoline

To a solution of7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)quinolin-4-ol (542 mg,1.84 mmol) in THF (9 mL) was added (S)-oxiran-2-ylmethanol (0.244 mL,3.67 mmol), triphenylphosphine (1267 mg, 3.67 mmol) and DIAD (0.714 mL,3.67 mmol). The reaction was stirred for 16 h at room temperature.Additional DIAD (0.200 mL, 1.03 mmol) was added. After 4 h, the reactionwas complete by LC/MS. The reaction mixture was concentrated and theresidue purified by column chromatography (40 g SiO₂, 0 to 30%CH₂Cl₂-acetone, gradient elution) to give4-(((R)-oxiran-2-yl)methoxy)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)quinoline(392.7 mg, 61%). ¹H NMR (400 MHz, CHLOROFORM-d) δ 8.85-8.78 (m, 1H),8.35 (d, J=8.6 Hz, 1H), 8.24-8.17 (m, 1H), 7.73-7.68 (m, 1H), 7.68-7.67(m, 1H), 6.81 (d, J=5.3 Hz, 1H), 6.49 (d, J=1.8 Hz, 1H), 5.36-5.28 (m,1H), 4.56 (ddd, J=11.1, 2.7, 0.9 Hz, 1H), 4.24-4.12 (m, 2H), 3.65 (td,J=11.7, 2.2 Hz, 1H), 3.54 (dq, J=6.0, 2.9 Hz, 1H), 3.06-3.00 (m, 1H),2.89 (dt, J=4.8, 2.4 Hz, 1H), 2.72-2.56 (m, 1H), 2.13-2.02 (m, 1H), 1.91(br d, J=13.1 Hz, 1H), 1.84-1.72 (m, 1H), 1.40-1.24 (m, 2H).

Step 3. Preparation of4-(((R)-oxiran-2-yl)methoxy)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)quinoline1-oxide

mCPBA (511 mg, 2.22 mmol) was added to a solution of4-(((R)-oxiran-2-yl)methoxy)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)quinoline(390 mg, 1.11 mmol) in CH₂Cl₂ (12.3 mL). The reaction was stirred for 2h, then quenched with saturated sodium thiosulfate solution. Thebiphasic mixture was stirred for 0.5 h, then saturated aqueous sodiumbicarbonate was added. The reaction was extracted twice with CH₂Cl₂. Thecombined organic layers were washed with brine, dried over sodiumsulfate, and concentrated to give4-(((R)-oxiran-2-yl)methoxy)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)quinoline1-oxide (408 mg, 1.11 mmol, quantitative yield). ¹H NMR (400 MHz,CHLOROFORM-d) δ 9.04-8.95 (m, 1H), 8.50 (d, J=6.9 Hz, 1H), 8.35 (dd,J=8.7, 0.7 Hz, 1H), 7.87 (dt, J=8.6, 1.5 Hz, 1H), 7.67 (d, J=1.6 Hz,1H), 6.74 (d, J=6.9 Hz, 1H), 6.58 (d, J=1.8 Hz, 1H), 5.35-5.30 (m, 1H),4.68-4.54 (m, 1H), 4.26-4.19 (m, 1H), 4.15 (ddd, J=11.1, 6.2, 3.4 Hz,1H), 3.84-3.73 (m, 1H), 3.56-3.49 (m, 1H), 3.04 (t, J=4.5 Hz, 1H),2.90-2.85 (m, 1H), 2.70-2.57 (m, 1H), 2.12-2.04 (m, 1H), 1.92 (br d,J=12.4 Hz, 1H), 1.85-1.73 (m, 1H), 1.38-1.25 (m, 2H)

Step 4. Preparation of4-((R)-2-hydroxy-3-morpholinopropoxy)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)quinoline1-oxide

4-(((R)-oxiran-2-yl)methoxy)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)quinoline1-oxide (59 mg, 0.16 mmol), ethanol (1.6 mL) and morpholine (16.8 mg,0.193 mmol) was added to a 2 dram pressure vial and the reaction mixturewas heated at 60° C. After 3 hours, the reaction was complete by LC/MS.The reaction mixture was concentrated and the residue was dissolved insmall amount of CH₂Cl₂ followed by the addition of Et₂O which resultedin the formation of a solid. The supernatant was decanted and the solidwashed with Et₂O. The solid was dried to give4-((R)-2-hydroxy-3-morpholinopropoxy)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)quinoline1-oxide (42.7 mg, 59%). ¹H NMR (400 MHz, CHLOROFORM-d) δ 9.05-8.95 (m,1H), 8.51 (d, J=6.8 Hz, 1H), 8.31 (d, J=8.6 Hz, 1H), 7.85 (dd, J=8.6,1.1 Hz, 1H), 7.67 (d, J=1.7 Hz, 1H), 6.74 (d, J=6.9 Hz, 1H), 6.62-6.51(m, 1H), 5.34-5.31 (m, 1H), 4.35-4.28 (m, 1H), 4.27 (s, 1H), 4.21 (dt,J=11.4, 2.0 Hz, 1H), 3.81-3.75 (m, 4H), 2.80-2.72 (m, 2H), 2.69-2.64 (m,2H), 2.63-2.57 (m, 1H), 2.57-2.49 (m, 2H), 2.12-2.05 (m, 2H), 1.92 (brd, J=12.9 Hz, 2H), 1.78 (dt, J=7.9, 4.0 Hz, 2H), 1.59 (br dd, J=9.6, 3.3Hz, 2H).

Step 5. Preparation of(2R)-1-((2-amino-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)quinolin-4-yl)oxy)-3-morpholinopropan-2-ol

To a solution of4-((R)-2-hydroxy-3-morpholinopropoxy)-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)quinoline1-oxide (42 mg, 0.092 mmol) in CH₂Cl₂ was added ammonia hydroxide (30%)solution (0.9 mL, 14.3 mmol) followed by tosyl chloride (35.2 mg, 0.185mmol). After 20 min, the reaction was complete by LC/MS. The reactionmixture was diluted with CH₂Cl₂ and water, and extracted two times withCH₂Cl₂. The combined organic layers were dried over sodium sulfate, andconcentrated to give the crude(2R)-1-((2-amino-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)quinolin-4-yl)oxy)-3-morpholinopropan-2-ol(25 mg, 60%). LC RT: 0.56 min. M/Z=454.5

Step 6: Preparation of(R)-1-((2-amino-7-(1H-pyrazol-5-yl)quinolin-4-yl)oxy)-3-morpholinopropan-2-ol(Compound 349)

To a solution of the crude(2R)-1-((2-amino-7-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)quinolin-4-yl)oxy)-3-morpholinopropan-2-ol(25 mg, 0.055 mmol) in CH₂Cl₂ (0.7 mL) was added TFA (350 μL, 4.54 mmol)and the reaction mixture was stirred at rt. After 1 hour, the reactionwas complete by LCMS. The reaction was concentrated and azeotroped withCH₂Cl₂(1×). The residue was dissolved in DMF, filtered through a syringefilter, and the crude material was purified via preparative LC/MS withthe following conditions: Column: XBridge C18, 200 mm×19 mm, 5-μmparticles; Mobile Phase A: 5:95 acetonitrile:water with 0.1%trifluoroacetic acid; Mobile Phase B: 95:5 acetonitrile:water with 0.1%trifluoroacetic acid; Gradient: a 0-minute hold at 0% B, 0-40% B over 20minutes, then a 4-minute hold at 100% B; Flow Rate: 20 mL/min; ColumnTemperature: 25° C. Fraction collection was triggered by MS signals.Fractions containing the desired product were combined and dried viacentrifugal evaporation to give(R)-1-((2-amino-7-(1H-pyrazol-5-yl)quinolin-4-yl)oxy)-3-morpholinopropan-2-ol(12.7 mg, 62%). ¹H NMR (500 MHz, DMSO-d₆) δ 8.16 (d, J=8.2 Hz, 1H), 7.99(s, 1H), 7.90 (br d, J=7.9 Hz, 1H), 7.83 (br s, 1H), 6.87 (d, J=2.1 Hz,1H), 6.36 (s, 1H), 4.50-4.42 (m, 1H), 4.29-4.20 (m, 2H), 3.32-3.20 (m,2H), 2.94-2.87 (m, 1H). Some aliphatic protons are not visible in the¹H-NMR due to to overlap with the water peak. LC RT: 0.96 min.M/Z=370.22.

Example III-20: Preparation of3-((2-amino-7-(1H-pyrazol-5-yl)quinolin-4-yl)amino)-1-morpholinopropan-1-one(Compound 350)

Step 1: Preparation of tert-butyl3-((2-amino-7-bromoquinolin-4-yl)amino)propanoate

To a solution of 7-bromo-4-chloroquinolin-2-amine (100 mg, 0.388 mmol)and tert-butyl-3-aminopropanoate hydrochloride (353 mg, 1.942 mmol) inDMSO (1 mL) was added hunig's base (0.678 mL, 3.88 mmol). The reactionwas heated to 120° C. overnight. The reaction was cooled, evaporated anddried under high vaccum. The residue was purified via ISCO (24 g column;Hexanes/Ethyl acetate; 0 to 100% gradient then 0 to 20% DCM/MeOH) togive tert-butyl 3-((2-amino-7-bromoquinolin-4-yl)amino)propanoate (140mg, 0.38 mmol, 98%).

Step 2: Preparation of3-((2-amino-7-(1H-pyrazol-5-yl)quinolin-4-yl)amino)propanoic acid

In a pressure vials was placed1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(133 mg, 0.478 mmol), tert-butyl3-((2-amino-7-bromoquinolin-4-yl)amino)propanoate (140 mg, 0.382 mmol),and PdCl₂(dppf)-CH₂Cl₂ adduct (31.2 mg, 0.038 mmol). The vial was placedunder vacuum and backfilled with nitrogen three times. Dioxane (5 ml)and tripotassium phosphate (2M aq) (0.573 mL, 1.147 mmol) were added,nitrogen was bubbled through the solution, then the reaction was heatedto 100° C. overnight. The reaction was cooled to room temperature,diluted with 50 ml of DCM, dried with sodium sulfate, and concentrated.The residue was purified via ISCO (24 g column; DCM/MeOH; 0 to 40%gradient). After evaporation, the residue was dissolved in dioxane (5ml). To this solution was added HCl (4N dioxane) (3 mL, 12.00 mmol).After 16 hours, the reaction mixture was concentrated under reducedpressure and dried under high vaccum.

Step 3: Preparation of3-((2-amino-7-(1H-pyrazol-5-yl)quinolin-4-yl)amino)-1-morpholinopropan-1-one(Compound 350)

A solution of3-((2-amino-7-(1H-pyrazol-5-yl)quinolin-4-yl)amino)propanoic acid (35mg, 0.118 mmol), morpholine (0.021 mL, 0.235 mmol), TBTU (113 mg, 0.353mmol), and TEA (0.164 mL, 1.177 mmol) in DMF (1 mL) was stirred at roomtemperature for 4 hours. The reaction mixture was diluted with 0.5 ml ofDMF and 0.5 ml of acetic acid, filtered through a syringe filter, andthe crude material was purified via preparative LC/MS with the followingconditions: Column: XBridge C18, 200 mm×19 mm, 5-μm particles; MobilePhase A: 5:95 acetonitrile:water with 0.1% trifluoroacetic acid; MobilePhase B: 95:5 acetonitrile:water with 0.1% trifluoroacetic acid;Gradient: a 0-minute hold at 0% B, 0-25% B over 35 minutes, then a4-minute hold at 100% B; Flow Rate: 20 mL/min; Column Temperature: 25 C.Fraction collection was triggered by MS signals. Fractions containingthe desired product were combined and dried via centrifugal evaporationto give3-((2-amino-7-(1H-pyrazol-5-yl)quinolin-4-yl)amino)-1-morpholinopropan-1-onebis-trifluoroacetate (11.3 mg, 26%) ¹H NMR (500 MHz, DMSO-d₆) δ8.25-8.18 (m, 1H), 8.04 (br s, 1H), 7.96 (br s, 1H), 7.93-7.81 (m, 2H),7.70-7.61 (m, 1H), 6.86 (s, 1H), 5.85 (s, 1H), 3.62-3.51 (m, 4H), 3.48(br d, J=7.3 Hz, 2H), 2.80 (t, J=7.0 Hz, 2H) Three methylenes are notvisible, likely due to overlap with suppressed water peak. LC/MSconditions: Column: Waters XBridge C18, 2.1 mm×50 mm, 1.7 μm particles;Mobile Phase A: 5:95 acetonitrile:water with 10 mM ammonium acetate;Mobile Phase B: 95:5 acetonitrile:water with 10 mM ammonium acetate;Temperature: 50° C.; Gradient: 0% B to 100% B over 3 min, then a 0.50min hold at 100% B; Flow: 1 mL/min; Detection: MS and UV (220 nm). LCRT: 0.97 min. M/Z=367.11.

Evaluation of Biological Activity

Measurement of IL-1β Production in PMA-Differentiated THP-1 Cells THP-1cells were purchased from the American Type Culture Collection andsub-cultured according to instructions from the supplier. Prior toexperiments, cells were cultured in RPMI 1640 containing 10% heatinactivated FBS, penicillin (100 units/ml) and streptomycin (100 μg/ml),and maintained in log phase prior to experimental setup. Prior to theexperiment THP-1 were treated with PMA (Phorbol 12-myristate 13-acetate)(10 μg/ml) for 24 hours. The day of the experiment the media was removedand attaching cells were treated with trypsin for 2 minutes, cells werethen collected, washed with PBS (phosphate buffer saline), spin down,resuspended in 2% heat inactivated FBS with RPMI at a concentration of1×10⁶ cells/ml, and 100 μl was plated in a 96 well plate. Compounds weredissolved in dimethyl sulfoxide (DMSO) and added to the culture mediumto achieve desired concentration (e.g. 100, 30, 10, 3, 1, 0.3 or 0.1μM). Cells were incubated with compounds for 4 hours. Cell freesupernatant was collected and the production of IL-1β was evaluated byELISA. A vehicle only control was run concurrently with each experiment.Final DMSO concentration was 1%. Compounds exhibit a dose-relatedincrease of IL-1β production in PMA-differentiated THP-1 cells.

Measurement of IL-1β Production in PMA-Differentiated THP-1 Cells(Alternative Procedure)

THP-1 cells were purchased from the American Type Culture Collection andsub-cultured according to instructions from the supplier. Prior toexperiments, cells were cultured in RPMI 1640 containing 10% heatinactivated FBS, penicillin (100 units/ml), streptomycin (100 μg/ml),HEPES (10 mM) and sodium pyruvate (1 mM) and maintained in log phaseprior to experimental setup. Prior to the experiment, THP-1 cells weretreated with PMA (Phorbol 12-myristate 13-acetate) (20 μg/ml) overnight.The day of the experiment, the media was removed and attached cells weretreated with trypsin for 2 minutes, cells were then collected, washedwith PBS (phosphate buffer saline), pelleted by centrifugation andresuspended in 2% heat inactivated FBS with RPMI at a concentration of50,000 cells/well in a 384 well plate. Cell free supernatant wascollected and the production of IL-1β was evaluated by ELISA. Compoundswere dissolved in dimethyl sulfoxide (DMSO) and added to the culturemedium to achieve desired concentration (e.g. 100, 30, 10, 3, 1, 0.3 or0.1 μM). Cells were incubated with compounds for 2 hours. A vehicle onlycontrol was run concurrently with each experiment. Final DMSOconcentration was 1%. Compounds exhibit a dose-related increase of IL-1βproduction in PMA-differentiated THP-1 cells.

Measurement of IL-1β Production—hTRF Protocol (Second AlternativeProcedure)

Serial dilutions of compounds in DMSO were added to low volume 384 wellplates at 100 nl/well using an ECHO 550 acoustic dispenser (Labcyte) toachieve final starting concentration of 10 μM in assay.

THP-1 cells in RPMI (Gibco, 11875) media with 10% FBS at a density of1×10⁶ cell/ml in a T175 flask were treated with a final concentration ofphorbol 12-myristate 13-acetate (PMA) (Sigma, P1585) of 50 ng/mlovernight at 37° C. at 5% CO₂ for differentiation. Cells were harvestedthe next day after rinsing well with dPBS using 0.5% trypsin. A cellsolution was prepared of 1×10⁶ cells/ml for 50,000 cells in 50 μl/wellin RPMI media with 2% FBS. Cells were plated using a multichannelpipette onto the compound dilutions in Greiner, 384 well, black clearbottom tissue culture treated plates (781090). The plates were incubatedin 37° C. incubator at 5% CO₂ for 2 hours.

After 2 hour incubation, the cell plates were spun in the centrifuge for5 minutes at 1200 rpm. Using the Felix (CyBio), 8 μl of the supernatantwas transferred to 384 well, low volume, white proxy plates. (PerkinElmer, 6008230). A human ILI beta hTRF kit was used to analyze thesupernatant (CISBIO, 62HIL1BPEG). The kit instructions were followed forpreparing the ILI Beta standard curve and then the antibodies from thekit were diluted 1:40 rather than 1:20 as kit instructed. Once combined,the antibodies were added across the plates, 5 μl/well. The plates weresealed and incubated at 4° C. overnight. The plates were then read onthe Perkin Elmer EnVision at 665/615 nm using the hTRF laser. Compoundsexhibited a dose-related increase of IL-1β production.

Measurement of IL-1β Production—Human Whole Blood Assay

Serial dilutions of compounds in DMSO were added to low volume 384 wellplates at 100nl/well using an ECHO 550 acoustic dispenser (Labcyte) toachieve final starting concentration of 10 uM in assay.

Human venous whole blood obtained from healthy donors was pre-treatedwith LPS (Invivogen, Cat #tlrl-eblps) at 1 ng/ml for four hours at 37°C. in a humidified 95% air/5% CO₂ incubator. Primed blood was added tothe compound plate and incubated for additional 4 hours at 37° C.IL-1beta in the supernatants was measured using AlphLISA kit (Cat#AL220) according to manufacturer's instructions. Compounds exhibited adose-related increase of IL-1β production. EC50 was determined usingprimed but untreated blood as baseline.

Measurement of IL-1β Production—Mouse hTRF Protocol

Immortalized mouse macrophages derived from C57BL/6 mice were obtainedfrom Ericke Latz, University of Bonn/University of MassachusettsWorchester, Mass. The cells were harvested using 0.05% Trypsin andwashed with PBS. Cell were plated at 30,000 cells per well in 25ul inDMEM (Gibco, 11965) supplemented with 2% FBS and incubated for 10minutes at 37° C. at 5% CO₂. LPS-EB (Invivogen, tlr-eblps) was added toa final concentration of 200 ng/ml at 5 ul/well and cells were incubatedfor 2 hours at 37° C. at 5% CO₂.

Serial dilutions of compounds in DMSO were added to cells in low volume384 well plates at 60nl/well using an ECHO 550 acoustic dispenser(Labcyte) to achieve final starting concentration of 50 uM in assay andincubated with compounds for additional 2 hours at 37° C. at 5% CO₂.

After 2 hour incubation, the cell plates were spun in the centrifuge for5 minutes at 1200 rpm. Using the Felix (CyBio), 8ul of the supernatantwas transferred to 384 well, low volume, white proxy plates. (PerkinElmer, 6008230). A human ILI beta hTRF kit was used to analyze thesupernatant (CISBIO, 62MIL1BPEH). The kit instructions were followed forpreparing the ILI Beta standard curve (the antibodies from the kit werediluted 1:40 rather than 1:20 as kit instructed). Once combined, theantibodies were added across the plates at 5 ul/well. The plates weresealed and incubated at 4° C. overnight. The plates were read on thePerkin Elmer EnVision at 665/615 nm using the hTRF laser. Data was thenconverted to pg/ml of Il1Beta. Compounds exhibited a dose-relatedincrease of IL-1β production.

In Vitro Human TLR7 and TLR8 Binding Reporter Assays

Logarithmically-growing human HEK-Blue cells co-expressing a TLR7 orTLR8 gene and a NF-kB/AP1-inducible SEAP (secreted embryonic alkalinephosphatase; Invivogen, San Diego, Calif.) reporter gene are added toindividual wells of a 384-well plate (15,000 cells per 20 μL per well)and maintained for 24 h at 37° C., 5% CO₂. Test compounds or DMSO aredistributed to separate wells the next day using acoustic liquidhandling technology (100 nL per well) and cells are subsequentlyincubated for 18 h at 37° C., 5% CO₂. Cellular SEAP production ismeasured using an Envision plate reader instrument thirty minutes afteradding freshly-made Quanti-Blue reagent (prepared by followingmanufacturer instructions; Invivogen, San Diego, Calif.) to the HEK-BlueTLR Nf-kB-SEAP cell reactions. All EC₅₀ values (half-maximal effectiveconcentration) are determined using proprietary data analysis software.Normalized EC₅₀ value=absolute value determined by setting 100% Ymaxusing a reference standard RLU (relative light unit) values from cellstreated with 50 μM of the reference standard.

Table 1 includes biological data of compounds that were assayed usingone or more of the above procedures. Key to activity ranges: A=≤1 μM;B=>1 μM, ≤20 μM; C=>20 μM, ≤100 μM; D=>100 μM; E: <50% activity at 50μM.

TABLE 1 NLRP3 TLR7 TLR8 COMPD_ hIL1B IC₅₀ Agonist EC₅₀ Agonist EC₅₀ NO(μM) (μM) (μM) 101 0.79 D D 102 1.38 D D 103 1.60 D D 104 0.69 D D 1052.98 D D 106 3.82 D D 107 0.34 D D 108 1.15 109 4.33 D D 110 1.64 D D111 2.46 D D 112 2.56 D D 113 11.90 D D 114 4.25 D D 115 3.04 D D 1164.07 D D 117 5.80 E E 118 1.73 D D 119 3.07 D C 120 4.24 E E 121 3.03 ED 122 1.87 E E 123 3.01 E E 124 14.51 D D 125 1.98 E E 126 3.53 E E 1271.15 D D 128 0.10 D D 129 2.29 D D 130 2.76 E D 131 0.85 D D 132 0.53 DD 133 0.30 D D 134 0.29 D D 135 0.12 D D 136 3.02 D D 137 0.55 D D 1385.95 B D 139 2.01 D D 140 1.41 D D 141 0.63 D D 142 1.43 D D 143 5.81 DD 144 0.48 D D 145 2.55 D D 146 4.07 D D 147 0.99 D D 148 1.64 D D 1490.14 D D 150 0.22 D D 151 0.31 D D 152 1.03 D D 153 1.11 D D 154 0.44 DD 155 0.42 D D 156 0.20 D D 157 0.73 D D 158 35.84 D D 159 0.52 D D 1602.76 D D 161 0.15 D D 162 2.49 D D 163 0.16 D D 164 1.91 D D 165 0.47 DD 166 0.56 D D 167 8.33 D D 168 2.40 E D 169 1.37 D D 170 5.82 D D 1710.38 E D 172 0.41 D D 173 0.28 D D 174 0.82 D D 175 0.97 D D 176 0.70 DD 177 3.07 D D 178 0.70 D D 179 0.78 D D 180 9.72 D D 181 9.92 E D 1821.14 D D 183 8.40 D D 184 7.27 E D 185 0.56 D D 186 1.08 D D 187 0.85 DD 188 6.31 D D 189 0.39 D D 190 0.66 D D 191 0.63 D D 192 0.63 D D 1931.69 D D 194 2.23 D D 195 0.93 D D 196 1.11 D D 197 2.86 D D 198 11.37 DD 199 13.30 D D 200 1.89 D D 201 5.05 D D 202 1.89 D D 203 0.19 D D 2040.64 D D 205 1.29 D D 206 0.84 D D 207 1.07 D D 208 1.55 D D 209 1.96 DD 210 20.75 D D 211 13.50 D D 212 9.27 D D 213 1.55 D D 214 4.61 D D 2151.94 D D 216 2.23 D D 217 14.35 D D 218 1.19 D D 219 2.75 D D 220 0.57 DD 221 0.52 D D 222 0.06 D D 223 1.35 D D 224 0.22 D D 225 0.13 D D 2260.73 D D 227 0.33 D D 228 0.16 D D 229 0.09 D D 230 0.54 D D 231 1.27 DD 232 0.23 D D 233 0.09 D D 234 0.23 D D 235 0.86 D D 236 2.65 D D 2372.57 D D 238 1.49 D D 239 4.83 D D 240 0.24 D D 241 2.25 D D 242 2.35 DD 243 1.02 D D 244 0.35 D D 245 1.34 D D 246 0.17 D D 247 0.48 D D 2480.33 D D 249 0.05 D D 250 1.72 D D 251 0.37 D D 252 1.69 D D 253 0.27 DD 254 0.21 D D 255 0.27 D D 256 0.22 D D 257 0.68 D D 258 1.84 D D 2590.64 D D 260 0.32 D D 261 0.14 D D 262 0.12 D D 263 2.87 D D 264 2.89 DD 265 0.35 D D 266 0.39 D D 267 1.59 D D 268 0.97 D D 269 1.15 D D 2707.37 D D 271 0.36 D D 272 6.22 D D 273 0.17 D D 274 1.98 D D 275 0.20 DD 276 0.52 D D 277 0.22 D D 278 1.31 D D 279 0.33 D D 280 1.57 D D 2810.58 D D 282 5.66 D D 283 1.70 D D 284 0.38 D D 285 1.56 D D 286 13.11 DD 287 0.70 D D 288 0.39 D D 289 0.85 D D 290 1.00 D D 291 1.67 D D 2920.34 D D 293 0.87 D D 294 0.21 D D 295 0.31 D D 296 0.56 D D 297 0.57 DD 298 0.15 D D 299 0.65 D D 300 0.54 D D 301 1.01 D D 302 0.05 D D 3030.14 D D 304 0.37 D D 305 0.64 D D 306 1.10 D D 307 0.11 D D 308 0.52 DD 309 0.42 D D 310 0.11 D D 311 3.13 D D 312 1.59 D D 313 0.11 D D 3141.80 D D 315 1.52 D D 316 0.56 D D 317 0.69 D D 318 0.07 D D 319 25.7 DD 320 27.68 D D 321 11.59 D D 322 0.61 D D 323 5.72 D D 324 1.76 D D 32523.16 D D 326 24.73 D D 327 4.66 D D 329 0.67 D D 330 24.59 D D 33114.62 D D 332 0.65 D D 333 1.31 D D 334 2.62 D D 335 0.63 D D 336 2.03 DD 337 9.17 D D 338 3.41 D D 339 0.48 D D 340 0.73 D D 341 0.62 D D 3421.10 D D 343 0.61 D D 344 1.11 D D 345 1.77 D D 346 0.76 D E 347 1.18 DD 348 7.26 D D 349 5.80 D D 350 4.19 D D 351 0.17 D

What is claimed is:
 1. A compound having formula (I), or apharmaceutically salt thereof:

wherein: W′ is H; W is independently selected from:

R³ is independently pyrazolyl, thienyl or isothiazolyl; R⁴ isindependently H or F; and R^(f) is independently H, CH₂CH₂OH, or—C(O)O(C₁₋₄ alkyl).
 2. The compound of claim 1, or a pharmaceuticallyacceptable salt thereof, wherein: W′ is H; W is independently selectedfrom:

R³ is independently pyrazolyl or thienyl; R⁴ is independently H or F;and R^(f) is independently H, CH₂CH₂OH, or —C(O)O(C₁₋₄ alkyl).
 3. Thecompound of claim 2, or a pharmaceutically acceptable salt thereof,wherein: W′ is H; W is independently selected from:

R³ is independently

R⁴ is independently H or F;
 4. The compound of claim 3, or apharmaceutically acceptable salt thereof, wherein: W′ is H; W isindependently selected from:

R³ is independently

and R⁴ is independently H or F.
 5. The compound according to claim 4, ora pharmaceutically acceptable salt thereof, wherein: W′ is H; W isindependently selected from:

R³ is independently

and R⁴ is independently H or F.
 6. The compound according to claim 5, ora pharmaceutically acceptable salt thereof, wherein: W′ is H; W is

R³ is

and R⁴ is H.
 7. A compound selected from:

or a pharmaceutically acceptable salt thereof.
 8. The compound accordingto claim 7, wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.
 9. A compound of theformula

or a pharmaceutically acceptable salt thereof.
 10. A pharmaceuticalcomposition comprising a compound or a pharmaceutically acceptable saltthereof as claimed in claim 1 and one or more pharmaceuticallyacceptable excipients.
 11. A method of treating cancer, comprisingadministering to a subject in need of such treatment an effective amountof a compound or a pharmaceutically acceptable salt thereof as claimedin claim
 1. 12. The method of claim 11, wherein the cancer is selectedfrom acute myeloid leukemia, adrenocortical carcinoma, Kaposi sarcoma,lymphoma, anal cancer, appendix cancer, teratoid/rhabdoid tumor, basalcell carcinoma, bile duct cancer, bladder cancer, bone cancer, braincancer, breast cancer, bronchial tumor, carcinoid tumor, cardiac tumor,cervical cancer, chordoma, chronic lymphocytic leukemia, chronicmyeloproliferative neoplasm, colon cancer, colorectal cancer,craniopharyngioma, endometrial cancer, ependymoma, esophageal cancer,esthesioneuroblastoma, Ewing sarcoma, eye cancer, fallopian tube cancer,gallbladder cancer, gastrointestinal carcinoid tumor, gastrointestinalstromal tumor, germ cell tumor, hairy cell leukemia, head and neckcancer, heart cancer, liver cancer, hypopharngeal cancer, pancreaticcancer, kidney cancer, laryngeal cancer, chronic myelogenous leukemia,lip and oral cavity cancer, lung cancer, melanoma, Merkel cellcarcinoma, mesothelioma, mouth cancer, oral cancer, osteosarcoma,ovarian cancer, penile cancer, pharyngeal cancer, prostate cancer,rectal cancer, salivary gland cancer, skin cancer, small intestinecancer, soft tissue sarcoma, testicular cancer, throat cancer, thyroidcancer, urethral cancer, uterine cancer, vaginal cancer, and vulvarcancer.
 13. The method of claim 11, wherein the cancer is a refractorycancer.
 14. The method of claim 11, wherein the cancer is selected frombreast cancer, colon cancer, rectal cancer, colorectal cancer,pancreatic cancer, and prostate cancer.
 15. The method of claim 11,wherein the cancer is selected from hormone receptor positive breastcancer, microsatellite stable colon or rectal cancer, pancreatic cancerand prostate cancer.
 16. The method of claim 11, wherein the compound isadministered in combination with one or more additional cancertherapies.
 17. The method of claim 16, wherein the one or moreadditional cancer therapies comprise surgery, radiotherapy,chemotherapy, toxin therapy, immunotherapy, cryotherapy or gene therapy,or a combination thereof.
 18. The method of claim 17, wherein theadditional cancer therapy comprises one or more agents selected fromnivolumab, pembrolizumab, PDR001, MEDI-0680, cemiplimab, JS001,BGB-A317, INCSHR1210, TSR-042, GLS-010, AM-0001, STI-1110, AGEN2034,MGD013, IBI308, BMS-936559, atezolizumab, durvalumab, avelumab,STI-1014, CX-072, LY3300054, CK-301, urelumab, PF-05082566, MEDI6469,TRX518, varlilumab, CP-870893, BMS-986016, MGA271, lirilumab, IPH2201,emactuzumab, INCB024360, galunisertib, ulocuplumab, BKT140, Bavituximab,CC-90002, bevacizumab, MNRP1685A, ipilimumab, MK-1308, AGEN-1884, andtremelimumab.
 19. The method of claim 16, wherein the additional cancertherapy comprises one or more agents selected from nivolumab,ipilimumab, pembrolizumab, atezolizumab, durvalumab and avelumab.